1,2-benzisoxazoloxyacetic acids and related compounds

ABSTRACT

Novel 1,2-benzisoxazoloxyacetic acids and related compounds, methods for preparing same and methods of treatment by administering compositions containing such a compound are described. These compounds are useful as diuretic, uricosuric and antihypertensive agents.

This is a continuation-in-part application of prior application Ser. No.949,128, filed Oct. 6, 1978, which is a continuation-in-part applicationof original application Ser. No. 853,313, filed Nov. 21, 1977 both nowabandoned.

This invention relates to novel 1,2-benzisoxazoloxyacetic acids andrelated compounds which are useful as diuretics, uricosurics, andantihypertensives, to methods of their preparation, to methods oftreatment with pharmaceutically effective amounts thereof and topharmaceutical compositions containing such a compound as an activeingredient.

To the best of our knowledge, the compounds of the present inventionhave not been heretofore made, described or suggested. Although1,2-benzisoxazoles are known, none are known which suggest the instantlydescribed compounds or their utility.

The compounds of this invention can be depicted by the general formula##STR1## in which R is hydrogen, loweralkyl, loweralkenyl, loweralkynyl,cycloalkyl, cycloalkenyl, bycycloalkyl, tricycloalkyl,cycloalkylloweralkyl, cycloalkenyloweralkyl, naphthyl, ##STR2## thienyl,furyl, pyrryl, pyridyl or pyridyl N-oxide; R¹ is a free or esterifiedcarboxyl group of from 1 to 8 carbon atoms, ##STR3## --CHO, --CH₂ OH,--CH(OR⁹)₂, --CN, ##STR4## R², R³ and R⁴ are the same or different andeach can be hydrogen, halogen or loweralkyl; X is hydrogen, halogen,loweralkyl, loweralkylthio, loweralkoxy, hydroxy, trifluoromethyl,nitro, amino or acylamino; R⁵, R⁶, R⁷, R⁸ and R⁹ are the same ordifferent and each can be hydrogen or loweralkyl; A and A' are the sameor different and may be O or S; Z is chlorine, bromine or fluorine; andm and n are the same or different and each can be the integer 1, 2 or 3.Also included within the scope of the present invention are thephysiologically acceptable salts of the above-depicted compounds whichare capable of forming same.

Some compounds within the scope of this invention have greaterpharmaceutical activity than others. Some of the latter, such as thosein which R¹ is an esterified carboxyl group CN, CH₂ OH or CHO arenevertheless desirable as intermediates for the preparation of the moreactive compounds. As indicated above, R may be a heterocyclic group suchas thienyl, fury, pyrryl or pyridyl, as well as an aliphatic orcarbocyclic group. A preferred group of compounds are those in which Ris an aromatic ring having an ortho fluoro with respect to the positionof attachment to the overall ring structure.

In the foregoing definitions and throughout this application thefollowing terms have the following meanings.

"Thienyl, furyl, pyrryl or pyridyl" means unsubstituted and substitutedmoieties wherein the substituents are halogen or loweralkyl;

"lower" means from 1 to 4 carbon atoms;

"cycloalkyl" means a saturated carbocyclic ring of from 3 to 8 carbonatoms;

"bicyclo- and tricycloalkyl," respectively, mean bi- and tricarbocyclicring systems containing from 7 to 10 carbon atoms; and

"cycloalkenyl" means an unsaturated carbocyclic ring of from 5 to 8carbon atoms.

The physiologically acceptable salts of this invention include thoseformed with an alkali or alkaline earth metal base or with a non-toxicorganic base such as ethanolamine, diethanolamine or N-methylglucamine.

The compounds of the present invention can be prepared by one of thefollowing multi-step sequences of reactions in which unless otherwiseindicated R, R¹ through R⁸, X, m and n are as previously defined and Yis chlorine or fluorine and ambient temperature means about 20°-25° C.

A. A phenol or alkoxybenzene of the formula ##STR5## in which R¹⁰ ishydrogen or loweralkyl, is reacted under Friedel-Crafts conditions withan acid halide of the formula

    RCOZ

in which R is as defined earlier and Z is chlorine, bromine or fluorineto provide a compound of the formula ##STR6## A preferred methodinvolves the use of 1,2-dichloroethane as a solvent and aluminumchloride as the Friedel-Crafts catalyst.

B. A compound of the formula R-H in which R is ##STR7## thienyl pyrrylor furyl is reacted under Friedel-Crafts conditions with an acid halideof the formula ##STR8## in which Y, Z and R¹⁰ are as defined in sequenceA, above, to provide a compound of the formula ##STR9## A preferredmethod involves use of 1,2-dichloroethane as a solvent and aluminumchloride as the Friedel-Crafts catalyst.

C. A compound of the formula ##STR10## in which R¹⁰ is loweralkyl isreacted with a compound of the formula R--MgZ or R--Li where R is nothydrogen followed by hydrolysis to afford a compound of Formula II.

Preferred conditions include use of tetrahydrofuran as solvent at atemperature of -70° C. to ambient.

D. A compound of Formula II in which R is hydrogen and R¹⁰ is loweralkylis reacted according to Method C to provide a compound of the formula##STR11## where R is not hydrogen.

E. A compound as prepared in Method D is oxidized to provide a compoundof Formula II wherein R is not hydrogen. One such method involves use ofchromium trioxide in glacial acetic acid.

F. A compound of Formula I or II in which R¹⁰ is loweralkyl, can bedealkylated by methods known in he art to obtain the correspondingcompound I or II in which R¹⁰ is hydrogen. One such method involvestreating with aluminum chloride in benzene.

G. A compound of Formula I or II is treated with hydroxylaminehydrochloride in a solvent such as pyridine to provide the correspondingcompound of the formula ##STR12##

H. A compound of Formula III is cyclized by treatment with a base in thepresence of a solvent at a temperature of from ambient to reflux of thereaction medium to provide the corresponding bicyclic compound of theformula ##STR13## A preferred method of cyclizing utilizes the basesodium hydride in the solvent dimethylformamide-benzene mixture atreflux.

I. A diphenol or dialkoxybenzene of the formula ##STR14## wherein R²,R³, R⁴ and R¹⁰ are as previously defined is reacted according to theprocedure of Method A to provide a compound of the formula ##STR15##

J. A compound of the formula R-H in which R is ##STR16## thienyl, pyrrylor furyl is reacted under Friedel-Crafts conditions with an acid halideof the formula ##STR17## in which Z and R², R³, R⁴ and R¹⁰ are aspreviously defined to provide a compound of the formula ##STR18##

K. A compound of the formula ##STR19## in which R¹⁰ is loweralkyl istreated according to Method C to produce a corresponding compound offormula V.

L. A compound of Formula V wherein R is hydrogen and R¹⁰ is loweralkylis reacted according to Method C to provide a compound of the formula##STR20## in which R is not hydrogen.

M. A compound as prepared in Method L is oxidized to provide a compoundof formula V wherein R is not hydrogen. One such method involves the useof chromium trioxide in glacial acetic acid.

N. A compound of formula V in which R¹⁰ is loweralkyl can be selectivelydealkylated to provide the corresponding compound V in which R¹⁰ orthoto the carbonyl group is hydrogen or fully dealkylated to provide acompound as depicted in formula V in which both R¹⁰ groups are hydrogen.The former process can be effected by use of one equivalent of aluminumchloride, the latter by two equivalents, both processes occuring in suchsolvents as benzene.

O. A compound of formula V in which at least the R¹⁰ which is ortho tothe carbonyl group is hydrogen is treated according to the procedure ofMethod G to provide a compound of the formula ##STR21##

P. A compound of formula VI is acetylated to provide a compound of theformula ##STR22## in which R¹¹ is hydrogen, loweralkyl or acetyl.

A preferred method utilizes acetic anhydride as a reactant and solvent.

Q. A compound of formula VII is cyclized by treatment with a base in thepresence of a solvent at a temperature of from ambient to reflux of thereaction mixture to provide the corresponding bicyclic compound##STR23##

R. A compound of formula IV in which R¹⁰ is loweralkyl can bedealkylated to afford the corresponding compound in which R¹⁰ ishydrogen. One preferred method is treatment with pyridine hydrochlorideat 170°-200° C.

S. A compound of formula IV in which R¹⁰ is hydrogen is reacted with acompound of the formula ##STR24## wherein R¹ is a free or esterifiedcarboxyl group, CN, CH₂ OH, CH(OR⁹)₂ or CO₂ CH₂ CH(OH)CH₂ OH and R⁹ isloweralkyl in the presence of a base and a solvent to provide a compoundof the invention of the formula ##STR25## with R¹ so defined. Apreferred method utilizes sodium hydride as the base anddimethylformamide as the solvent.

T. A phenoxyalkanoic acid ester or nitrile of the formula ##STR26## istreated according to the procedure of Method A to provide a compound ofthe formula ##STR27## A preferred method is carried out with an aluminumchloride catalyst and carbon disulfide solvent.

U. A compound of formula I or II wherein R¹⁰ is hydrogen can be treatedaccording to the procedure of Method S to provide a compound of theformula ##STR28## in which R¹ is a free or esterified carboxyl group,CN, CH₂ OH or CH(OH⁹)₂.

V. A compound of the formula IX or X can be treated according to theprocedure of Method G to provide a compound of the formula ##STR29##

W. A compound of Formula XI is treated according to the procedure ofMethod H to provide the corresponding compound of the invention of theformula VIII.

X. A compound of formula V in which R¹⁰ is H is treated according to theprocedure of Method S to provide a compound of the formula ##STR30##

Y. A compound of formula XII is treated according to the procedure ofMethod G to provide a compound of the formula ##STR31##

Z. A compound of formula XIII is treated according to the procedure ofMethod P to provide a compound of the formula ##STR32##

AA. A compound of the formula XIV is treated according to the procedureof Method Q to provide a compound of the invention VIII.

BB. A compound of the formula V, as prepared in Method N, in which R ishydrogen is treated with hydroxylamine-o-sulfonic acid in a solvent sucha water to produce a compound of the formula IV.

CC. A compound of formula XII in which R is hydrogen is treatedaccording to the procedure of Method BB to produce a compound of theinvention VIII.

DD. A compound of formula IV in which R¹⁰ is hydrogen and X is otherthan hydroxy or amino is treated with a dialkylthiocarbamoyl halide inthe presence of a base to produce a compound of the formula ##STR33## inwhich R⁷ and R⁸ are loweralkyl.

A preferred method involves the use of dimethylthiocarbamoyl chloride indimethylformamide as a solvent and sodium hydride as the base.

EE. A compound of formula XV is thermally rearranged to a compound ofthe formula ##STR34## by heating as a melt.

FF. A compound of the formula XVI is hydrolyzed by an convenient methodknown to the art to provide a compound of the formula ##STR35##

One such method utilizes dilute sodium hydroxide as the hydrolyzingagent.

GG. A compound of formula XVII is treated according to the procedure ofMethod S to produce a compound of the invention of formula ##STR36##

HH. A compound of the formula ##STR37## as described in Method N whereinR¹⁰ is loweralkyl and X may not be amino or hydroxyl, is treatedsuccessively according to the methods of DD, EE and FF to yield acompound of the formula ##STR38##

II. A compound of Formula XIX is treated successively according toMethods G, P. Q and R to yield a compound of the formula ##STR39##

JJ. A compound of formula XX is treated according to Method S to yield acompound of the invention ##STR40##

KK. A compound of formula XX is successively treated according toMethods DD, EE and FF to yield a compound of the formula ##STR41##

LL. A compound of formula XXII is treated according to Method S to yielda compound of the invention of the formula ##STR42##

MM. A compound of the invention of the formula VIII, XVIII, XXI or XXIIIin which R¹ is a carboxylic acid ester or CN is readily converted to acorresponding compound in which R¹ is COOH.

One such suitable method is hydrolysis with a base such as sodiumhydroxide.

NN. A compound of the invention of the formula VIII, XVIII, XXI or XXIIIin which R¹ is CH(OR⁹)₂ is readily converted to a corresponding compoundin which R¹ is CHO.

One suitable method is hydrolysis with dilute mineral acid.

OO. A compound of the formula VIII in which X, R², R³ and R⁴ are notloweralkyl in which R¹ is CH₂ OH or as prepared in Method NN in which R¹is CHO is converted to a corresponding compound in which R¹ is COOH.

A suitable method is oxidation with potassium permanganate

PP. A compound of the invention of the formula ##STR43## in which R¹ isCOOH is readily converted to a compound in which R¹ is COZ. A suitablemethod is treatment with SOZ₂.

QQ. A compound of the formula ##STR44## in which R¹ is COZ is readilyconverted to the corresponding compound in which R¹ is ##STR45## viatreatment respectively with ##STR46## in the presence or absence of anacid scavenger.

RR. A compound of the invention of the formula ##STR47## in which R¹ isCN is readily converted to the corresponding compound in which R¹ is##STR48## A suitable method is the treatment with HN₃ indimethylformamide.

SS. A compound of the formula ##STR49## in which R¹ is COZ, ##STR50## orany other non-specifically defined group which is convertible by ahydrolytic procedure to a COOH group is converted to a compound of theinvention in which R¹ is COOH via acid or basic hydrolysis.

TT. A compound of the formula ##STR51## in which R¹ is COOH may beconverted to a salt via treatment in a suitable solvent with anappropriate organic or alkali/alkaline earth base.

UU. A compound of the formula ##STR52## in which R is ##STR53## R¹⁰ isloweralkyl and X is not hydroxy or amino is treated with a strong basefollowed by a suitable electrophile to provide a compound of the formula##STR54## in which R² is halogen or loweralkyl. A preferred base isn-butyllithium and preferred electrophiles include bromine, iodine,chlorine, N-halosuccinimides and alkylhalides.

VV. A compound of the formula ##STR55## in which R² is hydrogen orhalogen, R¹⁰ is hydrogen or loweralkyl, R is ##STR56## and X is halogenis treated with elemental halogen in a solvent such as acetic acid toprovide a compound of the formula ##STR57## wherein R³ and R⁴ or bothmay be halogen. WW. A compound of the invention of the formula ##STR58##in which m is 1 or 2 and X is not NO₂ is nitrated via treatment withnitric acid in glacial acetic acid to provide the corresponding compoundof the formula ##STR59##

XX. A compound of the invention of the formula ##STR60## in which R is##STR61## and X is alkoxy is dealkylated to provide a correspondingcompound of the invention in which X is hydroxy.

A method is the careful treatment with boron tribromide.

YY. A compound as described for the starting material of Method XX,above, except that X is nitro and may be reduced by any convenientmethod known to the art to provide the corresponding compound in which Xis amino. A method involves the use of iron filings in aqueous ethanolichydrochloric acid.

ZZ. A compound as described for the starting material of Method XX,above, except that X is amino and may be acylated by methods known tothe art to provide the corresponding compound of the invention in whichX is acylamino. A suitable method is acylation with an anhydride.

AAA. A compound formula IV in which R is pyridyl is treated with anoxidizing agent to provide a corresponding compound of formula IV inwhich R is ##STR62## One such suitable oxidizing agent is3-chloroperbenzoic acid.

BBB. A compound of formula VIII wherein R¹ is CN and R, R², R³, R⁴, R⁵and R⁶ are as hereinbefore is reacted with a hydroxylamine hydrohalidein the presence of a base and a solvent to provide a compound of theformula ##STR63## wherein R¹ is ##STR64## and R, R², R³, R⁴, R⁵ and R⁶are as above.

It can be appreciated that reaction times and exact reaction conditionsof any and all of the above reaction steps of the above-shown sequencesof reactions are dependent upon particular reactants and solventsinvolved.

All starting materials shown above are either known compounds or caneasily be prepared by routine methods known to the art from readilyavailable materials.

For example, a starting material applicable in sequence B, D, E, L and Mto produce a compound of the invention wherein the O--CH₂ --R¹ groupoccupies the 5-position in 2-chloro-5-methoxybenzoic acid. Such amaterial can be prepared from the readily available2-chloro-5-nitroaniline via procedures readily known to one skilled inthe art, e.g., diazotization and treatment with CuCN to afford2-chloro-5-nitrobenzonitrile; followed by reduction with iron filings inaqueous ethanolic hydrochloric acid to 5-amino-2-chlorobenzonitrile;followed by diazotization to give 2-chloro-5 hydroxybenzonitrile;followed by methylation with dimethylsulfate to give2-chloro-5-methoxybenzonitrile; concluded with hydrolysis to2-chloro-5-methoxybenzoic acid. It is readily apparent that otherrequired substituted alkoxy-ortho-halbenzoic acids,alkoxy(hydroxy)ortho-alkoxy(hydroxy)benzoic acids, -aldehydes, and-nitriles, and various halo-alkoxy(hydroxy)-, anddialkoxy(hydroxy)-benzenes can be readily obtained by similar sequencesor other common reactions shown to one skilled in the art.

The compounds of the invention are useful as diuretic agents due totheir ability to produce diuresis in mammals. Diuretic activity ismeasured in mice by a method similar to that described by C. M. Kagawaand M. J. Kalm, Arch. Intern, Pharmcodyn. 137, 241 (1962). Drugs aredosed orally to a group of 6 mice and the average volume of urineexcreted is compared to (divided by) the average volume excreted by apositive control group of 6 mice dosed orally with 1000 ml/kg or urea, aknown diuretic agent. The resulting drug/urea ratios if greater than oneare indicative of diuretic activity. The diuretic activity in this testof some of the compounds of this invention and of tienilic acid andethacrynic acid, standard diuretics, is illustrated in Table I.

                  TABLE I                                                         ______________________________________                                                            DOSE                                                                          MG/KG    DRUG/UREA                                        COMPOUND            P.O.     RATIO                                            ______________________________________                                        {[7-chloro-3-(2-fluorophenyl)-1,2-                                                                 4       2.2                                              benzisoxazol-6-yl]oxy}acetic acid                                                                 32       6.1                                              {[7-chloro-3-(2-thienyl)-1,2-                                                                     6.4      1.2                                              benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-phenyl-1,2-                                                                          64       2.0                                              benzisoxazol-6-yl)oxy]}acetic acid                                            {[7-chloro-3-(2-furyl)-1,2-                                                                       64       1.1                                              benzisoxazol 6-yl]oxy}acetic acid                                             {[7-chloro-3-(4-tolyl)-1,2-                                                                        4       1.2                                              benzisoxazol-6-yl]oxy}acetic acid                                                                 64       2.0                                              {[7-chloro-3-chlorophenyl)-1,2-                                                                   64       1.5                                              benzisoxazol-6-yl]oxy}acetic acid                                             }[7-chloro-3-(5-methyl-2-furyl)-1,2-                                                              64       2.0                                              benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(3-furyl)-1,2-                                                                       64       2.0                                              benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(2-chlorophenyl)-1,2-                                                                 4       1.3                                              benzisoxazol-6-yl]oxy}acetic acid                                                                 16       2.4                                                                  32       5.6                                              {[7-chloro-3-(2-tolyl)-1,2-                                                                       64       2.3                                              benzisoxazol-6-yl]oxy}acetic acid                                             [(3-benzyl-7-chloro-1,2-benzisoxazol-                                                             64       1.2                                              6-yl)]acetic acid                                                             {[7-chloro-3-(1-napthyl)-1,2-benz-                                                                64       1.1                                              isoxazol-6-yl]oxy}acetic acid                                                 {[7-chloro-3-(3-methyl-2-thienyl)-1,2-                                                            64       1.4                                              benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(2,6-difluorophenyl)-1,2-                                                             4       3.1                                              benzisoxazol-6-yl]oxy}acetic acid                                                                 64       7.0                                              [3-(2-fluorophenyl)-1,2-benzisoxazol-                                                              4       1.3                                              6-yl]oxy}acetic acid                                                                              64       4.6                                              {[3-(2-fluorophenyl)-7-methyl-1,2-                                                                 8       2.1                                              benzisoxazol-6-yl]oxy}acetic acid                                                                 64       6.4                                              {[3-(2-fluorophenyl)-7-iodo-1,2-                                                                  64       2.3                                              benzisoxazol-6-yl]oxy}acetic acid                                             {[7-bromo-3-(2-fluorophenyl)-1,2-                                                                  4       1.7                                              benzisoxazol-6-yl]oxy}acetic acid                                                                 64       6.2                                              {[7-chloro-3-trans-β-fluorostyrl)-1,2-                                                       64       1.0                                              benzisoxazol-6-yl]oxy}acetic acid                                             {[5,7-dichloro-3-(2-fluorophenyl)-1,2-                                                            64       3.1                                              benzisoxazol-6-yl]thio}acetic acid                                            Tienilic Acid       64       1.8                                                                  16       1.2                                              Ethacrynic Acid     64       2.5                                              ______________________________________                                    

Such utility is effected when a compound of the invention isadministered to a patient requiring appropriate treatment at an oral,parenteral or intravenous dose of from 0.1-500 mg/kg of body weight perday. Preferred ranges include 1.0-200 mg/kg of body weight per day.

Compounds of the invention ae also useful as antihypertensive agents dueto their ability to depress blood pressure in mammals. Antihypertensiveactivity is measure in the spontaneous hypertensive rat by the indirecttail cuff method described by A. Schwartz, Ed., Methods inPharamacology, Vol, I, page 135, Appleton-Century-Crofts, New York, N.Y.1971. In this procedure a group of 5 animals are treated orally with thedrug for 3 days in relation to a control group of the same number. Thedrop in blood pressure is measured on the third day followingadministration. The antihypertensive activity expressed as mm decreasein mean arterial blood pressure in this test of some of the compounds ofthis invention is illustrated in Table II.

                                      TABLE II                                    __________________________________________________________________________                                 BLOOD PRESSURE                                                                DECREASE                                         COMPOUND             MG/KG P.O.                                                                            mm/HG                                            __________________________________________________________________________    {[7-chloro-3-phenyl-1,2-                                                                           50      15                                               benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(2-furyl)-1,2-                                                                        50      22                                               benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(4-tolyl)-1,2-                                                                        50      16                                               benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(4-chlorophenyl)-1,2-                                                                 50      16                                               benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(5-methyl-2-thienyl)-1,2-                                                             50      53                                               benzisoxazol-6-yl]oxy}acetic acid                                                                  10      35                                               [(3-benzyl-)-chloro-1,2-benzisoxazol-                                                              50      27                                               6-yl)oxy[acetic acid                                                          {[7-chloro-3-(1-napthyl)-1,2-benzisoxazol-                                                         50      39                                               6-yl]oxy}acetic acid                                                          {[7-chloro-3-(2,3-dimethylphenyl)-1,2-                                                             50      21                                               benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(4-fluorophenyl)-1,2-                                                                 50      19                                               benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(2-pyridyl)-1,2-benzisoxazol-                                                         50      21                                               6-yl]oxy}acetic acid oxide                                                    {[3-(2-fluorophenyl)-7-methyl-1,2-benzisoxa-                                                       50      28                                               zol-6-yl]oxy}acetic acid                                                      {[7-chloro-3-(trans-β-fluorostyryl)-1,2-                                                      50      27                                               benzisoxazol-6-yl]oxy}acetic acid                                             __________________________________________________________________________

Such utility is effected when a compound of the invention isadministered to a patient requiring appropriate treatment at an oral,parenteral or intravenous dose of from 0.1-500 mg/kg of body weight perday. Preferred ranges include 1.0-200 mg/kg of body weight per day.

The compounds of the invention are further useful as uricosuric agentsdue to their ability to cause increased uric acid excretion in mammals.Uricosuric activity is measured in a procedure whereby groups of sixWistar rats are dosed orally with the test compound suspended ordissolved in sufficient distilled water such that the volume dosed isequivalent to 25 ml/kg. A corresponding control group is dosed withwater only at this level. Urine is collected for five hours and uricacid content determined on an Abbott Biochromatic Analyzer usingUricosquant® reagent. The results for each group are expressed asaverage mg of uric acid excreted/kg of rat. Treated groups are comparedwith control groups for statistical significance. In general, values of2.5 mg U.A./kg or greater are considered to indicate uricosuricactivity. Representative data is given in Table III.

                  TABLE III                                                       ______________________________________                                                              DOSE     MG                                             COMPOUND              MG/KG    U.A./KG.                                       ______________________________________                                        {[7-chloro-3-(2-thienyl)-1,2-                                                                       256      3.5                                            benzisoxazol-6-yl]oxy}acetic acid                                             [7-chloro-3-phenyl-1,2-benzisoxa-                                                                   128      2.6                                            zol-6-yl)oxy]acetic acid                                                      }[7-chloro-3-(2-furyl-1,2-benzisoza-                                                                128      2.5                                            zol-6-yl]oxy}acetic acid                                                      {[7-chloro-3-(5-methyl-2-thienyl)-1,2-                                                              128      3.4                                            benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(3-furyl)-1,2-benzisoxazol-                                                            128      2.7                                            6-yl]oxy}acetic acid                                                          {[7-chloro-3-(2-fluorophenyl)-1,2-                                                                   64      3.3                                            benzisoxazol-6-yl]oxy}acetic acid                                                                   128      4.0                                                                  256      5.7                                                                  512      13.5                                           {[7-chloro-3-(4-fluorophenyl)-1,2-                                                                   32      3.0                                            benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(2,6-difluorophenyl)-1,2-                                                               64      2.5                                            benzisoxazol-6-yl]oxy}acetic acid                                             {[7-chloro-3-(2,4-difluorophenyl)-1,2-                                                               64      4.4                                            benzisoxazol-6-yl]oxy}acetic acid                                             {[3-(2-fluorophenyl)-1,2-benzisoxazol-6-                                                            128      2.5                                            yl]oxy}acetic acid                                                            {[5,7-dichloro-3-(2-fluorophenyl)-1,2-                                                              128      3.8                                            benzisoxazol-6-yl]thio}acetic acid                                            Tienilic Acid          64      2.9                                            Ethacrynic Acid       inactive                                                ______________________________________                                    

Such utility is effected when a compound of the invention isadministered to a patient requiring appropriate treatment at an oral,parenteral or intravenous dose of from 0.1-500 mg/kg of body weight perday. Preferred ranges include 1.0-200 mg/kg of body weight per day.

It is noteworthy that a significant advantage of these compounds istheir dual ability as diuretics and uricosurics. As is known, manypaitents experience an increase in uric acid concentration of the bloodduring treatment with most of the currently marketed diuretics. Elevateduric acid levels are a serrious problem in patients with goutyarthritis. Additionally, elevated uric acid levels are increasinglybeing considered a risk factor in cardiovascular disease. Accordingly,this concomitant ability to produce diuresis and increase uric acidexcretion represents a major advantage of the compounds disclosedherein. Compounds of the invention include:

{[7-chloro-3-(1-buten-2-yl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

[(7-chloro-3-ethyl-1,2-benzisoxazol-6-yl)oxy]acetic acid;

[(7-chloro-3-cyclopropyl-1,2-benzisoxazol-6-yl)oxy]acetic acid;

[(7-chloro-3-cyclohexyl-1,2-benziosoxazol-6-yl)oxy]acetic acid;

{[7-chloro-3-(2-norbornyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[3-(1-adamantyl)-7-chloro-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[7-chloro-3-(1-cyclohexen-1-yl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

[(7-chloro-3-cyclopropylmethyl-1,2-benzisoxazol-6-yl)oxy]acetic acid;

[(7-chloro-3-cyclopentylmethyl-1,2-benzisoxazol-6-yl)oxy]acetic acid;

{[7-chloro-3-(2-cyclopenten-1-methyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid;

[(7-chloro-3-propargyl-1,2-benzisoxazol-6-yl)oxy]acetic acid;

{[7-chloro-3-(4-methoxyphenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[7-chloro-3-(4-hydroxy-2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid;

{[7-chloro-3-(3-trifluoromethylphenyl)-1,2-benzisoxazol-yl]oxy}aceticacid;

{[7-chloro-3-(4-nitrophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[7-chloro-3-(4-aminophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[7-chloro-3-(4-acetamidophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[4,5-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[(4,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid;

[(4-methyl-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetic acid

[(5-methyl-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetic acid

{[7-chloro-3-(2-pyrryl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

[(3-phenyl-1,2-benzisoxazol-4-yl)oxy]acetic acid;

[(3-phenyl-1,2-benzisoxazol-5-yl)oxy]acetic acid;

[(3-phenyl-1,2-benzisoxazol-7-yl)oxy]acetic acid;

benzyl [7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy acetate;

n-propyl}3-(2-thienyl)-1,2-benziosxazole-6-yl]oxy}acetate

t-butyl[(3-phenyl-1,2-benziosoxazol-7-yl)oxy]acetate.

{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloride;

{[7-bromo-3-(2-fluoro-4-hydroxyphenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid;

{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide;

N,N-diethyl-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide;

2-{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethanol;

1,1-diethoxy-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}ethane;

{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetaldehyde;

{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetonitrile;

N-hydroxy-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide

N-amidino-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide;

5-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxymethyl}tetrazole;

{[7-bromo-5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid;

{[7-bromo-5-methyl-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid;

glyceryl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate;

{[7-chloro-3-(2-fluorophenyl)-1,2-benzisothiazol-6-yl]thio}acetic acid;

{[7-bromo-3-(2-fluorophenyl)-1,2-benzisothiazol-6-yl]thio}acetic acid;

{[7-bromo-3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[7-methyl-3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[7-bromo-3-(2,3-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;

{[7-bromo-3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.

{[7-chloro-3-(2-fluorophenyl)-1,2-benzisothiazol-6-yl]oxy}acetic acid;

{[7-bromo-3-(2-fluorophenyl)-1,2-benzisothiazol-6-yl]oxy}acetic acid;

{[7-chloro-3-[4-(methylthio)phenyl]-1,2-benzisoxazol-6-yl]oxy}aceticacid;

{[7-fluoro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid; and

{[7-chloro-3-(3-fluoro-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.

Effective quantities of the compounds of the invention may beadministered to a patient by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free acid final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable salts for purposes of stability, convenienceof crystallization, increased solubility and the like.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; and excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied to be between 0.5 and about 30% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The present invention is further illustrated by the following examplesof representative compounds and procedures.

EXAMPLE 1

a. To a solution of 31.6 g of 2-fluorobenzoyl chloride in 100 ml ofdichloroethane there is added incrementally 26.5 g of aluminum chlorideover a 30 minute period. Upon completion of the addition the mixtureturns yellow and then darkens. Thereafter to this darkened mixture thereis added dropwise a solution of 32 g of 2,3-dichloroanisole in 50 ml of1,2-dichloroethane. After the addition is complete the mixture isstirred for 2 hours before being poured over a mixture of 100 ml ofconcentrated hydrochloric acid and 100 ml of crushed ice.

The organic phase of the two-phase mixture is evaporated under vacuumand the aqueous mixture is extracted with either. The combined etherextracts successively are washed with a 10% potassium carbonatesolution, washed with water and dried and the ether is evaporated todryness leaving an off-white solid which is recrystallized from anether-hexane mixture to yield the product2'-fluoro-4-methoxy-2,3-dichlorobenzophenone having a melting point of74° to 77° C.

b. To a mixture of 38.5 g of2'-fluoro-4-methoxy-2,3-dichlorobenzophenone and 34.7 g of aluminumchloride in 250 ml of benzene is refluxed for 5 hours, then poured overa mixture of 100 ml of concentrated hydrochloric acid and 100 ml of ice.The two-phase mixture is extracted with ethyl acetate and the combinedextracts are dried and concentrated to dryness leaving a solid residue.The residue is triturated with hexane and the resulting solid isrecrystallized from an ether-hexane mixture to yield the product2,3-dichloro-4-hydroxy-2'-fluoro-benzophenone having a melting point of128° to 131° C.

c. A solution of 31.8 g of 2,3-dichloro-4-hydroxy-2'-fluoro-benzophenoneand 15.3 g of hydroxylamine hydrochloride in 150 ml of pyridine isrefluxed for 64 hours. Thereafter the pyridine is evaporated undervacuum and a 5% aqueous hydrochloric acid solution is added. Theacidified solution is extracted with ethyl acetate and the combinedextracts are dried before being concentrated to dryness. The resultingsolid is recrystallized from an aqueous ethanol solution to yield theproduct 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime with amelting point of 168° to 175° C.

d. A solution of 18.4 g of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenoneoxime and 3.6 g of sodium hydride in 120 ml of dimethylformamide and 120ml of benzene is maintained at a temperature of from 80°-85° C. for 3hours. Thereafter, the mixture is permitted to reach ambient temperatureafter which a solution of 11.0 g of ethyl bromoacetate in 20 ml ofdimethylformamide is added dropwise. After the addition is complete, themixture is stirred for 30 minutes and then water is added to decomposeany excess sodium hydride. The mixture is extracted with ethyl acetateand the combined extracts are dried and evaporated to dryness leaving asolid residue. The residue is recrystallized several times from 95%ethyl alcohol to yield the pure productethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetatehaving a melting point of 102° to 104° C.

Analysis: Calculated for C₁₇ H₁₃ ClFNO₄ : 58.38%C; 3.75%H; 4.01N. Found:58.11%C; 3.62%H; 3.86%N.

EXAMPLE 2

A mixture of 10.0 g ofethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate,100 ml of 10% sodium hydroxide, and 350 ml of ethyl alcohol is refluxedfor 3.5 hours. Thereafter, the ethyl alcohol is removed under vacuum andthe residue is acidified with a 5% hydrochloric acid solution effectinga solid precipitate. The precipitate is collected by filtration anddried. The dried product is recrystallized from 95% ethyl alcohol toyield the product{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acidhaving a melting point of 190° to 191° C.

EXAMPLE 3

a. To a mixture of 12.5 g of aluminum chloride and 45 ml of carbondisulfide there is added dropwise 7.1 g of 2-fluorobenzoyl chloridewhile maintaining the temperature below 0° C. This low temperature ismaintained for 1.5 hours. While maintaining this same low temperature, 5g of 2,3-dichlorophenoxyacetic acid is added incrementally. Afteraddition is complete, the reaction mixture is maintained at lowtemperature for 30 minutes and then permitted to reach ambienttemperature after which it is refluxed for 28 hours. The carbondisulfide is decanted from the refluxed solution leaving a dark orangeresidue which is poured onto a mixture of 500 ml of ice/water and 100 mlof concentrated hydrochloric acid. The resulting pink precipitate iscollected by filtration, rinsed with 300 ml of warm water (50° C.) anddried in vacuum oven. The dried product is recrystallized twice fromaqueous ethyl alcohol to form the product2,3-dichloro-4-(2-fluorobenzoyl)phenoxyacetic acid having a meltingpoint of 153° to 156° C.

b. A mixture of 1.0 g of 2.3-dichloro-4-(2-fluorobenzoyl)phenoxyaceticacid and 1 g of hydroxylamine hydrochloride in 10 ml of pyridine isrefluxed for 2 hours. Thereafter, the solvent is evaporated in vacuo andthe residue is stirred for 16 hours with 5% hydrochloric acid. Theproduct is filtered off and the collected solid is recrystallized fromaqueous ethyl alcohol to give the product2,3-dichloro-4-(2-fluorobenzohydroximoyl)phenoxyacetic acid having amelting point of 91° to 96° C.

c. A mixture of 0.3 g of2,3-dichloro-4-(2-fluorobenzohydroximoyl)phenoxyacetic acid and 0.05 gof sodium hydride in 5 ml of benzene and 5 ml of dimethylformamide isrefluxed for 3 hours. To the mixture, after it has been permitted tocool there is added 5% hydrochloric acid causing the benzene toseparate. The benzene is evaporated in vacuo and the resultingprecipitate is collected by filtration and recrystallized from aqueousethyl alcohol to yield the product{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acidhaving a melting point of 188° to 189° C.

Analysis: Calculated for C₁₅ H₉ ClFNO₄ : 56.00%C; 2.83%H; 4.36%N; Found:55.94%C; 2.86%H; 4.32%N

EXAMPLE 4

a. A mixture of 3.8 g of (2,3-dichloro-4-hydroxyphenyl)2'-thienylmethanone and 2.0 g of hydroxylamine hydrochloride in 20 ml ofpyridine is refluxed for 6 hours. Thereafter, the pyridine is evaporatedin vacuo. To the residue there is added 5% hydrochloric acid and theacidified mixture is extracted with ethyl acetate. The extract,sequentially, is washed with water, dried and evaporated to dryness. Theresidue is recrystallized from an ethanol and water mixture to yield theproduce (2,3-dichloro-4-hydroxyphenyl)-2'-thienylmethanone oxime havinga melting point of 179° to 183° C.

b. To a mixture of 3.0 g of(2,3-dichloro-4-hydroxyphenyl)-2'-thienylmethanone oxime in 30 ml ofdimethylformamide and 30 ml of toluene is added 0.62 g of sodiumhydride. Thereafter, the reaction mixture is maintained at 100° C. for 2hours and then at 115° C. for 2.5 hours. The mixture is permitted tocool prior to adding thereto dropwise a solution of 1.9 g of ethylbromoacetate in 10 ml of dimethylformamide. After addition is complete,the reaction mixture is stirred for 2.25 hours and then water is addedto decompose any excess sodium hydride. The reaction mixture isextracted with ethylacetate and the extract is, sequentially, washedwith water, dried and evaporated. The residue is recrystallized fromethanol to yield the productethyl{[7-chloro-3-(2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetate having amelting point of 142° to 143° C.

Analysis: Calculated for C₁₅ H₁₂ ClNO₄ S: 53.33%C; 3.58%H; 4.15%N;Found: 53.28%C; 3.58%H; 4.17%N

EXAMPLE 5

a. A solution of 18.0 g of 2,3-dichloro-4-hydroxybenzophenone and 9.3 gof hydroxylamine hydrochloride in 100 ml of pyridine is refluxed for 2hours. Thereafter, the pyridine is evaporated under vacuum and theresidual liquid is partitioned between 5% hydrochloric acid and ethylacetate. The ethylacetate extract is washed with water, dried, andevaporated to give 2,3-dichloro-4-hydroxy-benzophenone oxime.

Said 2,3-dichloro-4-hydroxybenzophenone is prepared in a mannerconsistent with the procedure described in Example 1(a) and (b) withbenzoyl chloride replacing 2-fluorobenzoyl chloride.

b. A solution of 2,3-dichloro-4-hydroxybenzophenone oxime and 2.6 g ofsodium hydride in 50 ml of dimethylformamide and 50 ml of toluene isheated to 118° C. and maintained at this temperature for 50 minutes.Thereafter, the reaction is permitted to cool prior to the dropwiseaddition of 7.9 g of ethyl bromoacetate in 50 ml of dimethylformamide.After the addition is complete the reaction mixture is stirred atambient temperature for 40 minutes. To the well stirred mixture water isadded dropwise to decompose any excess sodium hydride. The toluene isevaporated under vacuum and the resulting precipitate is collected byfiltration and then rinsed with ether to yield the productethyl[(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetate having amelting point of 130° to 132° C.

Analysis: Calculated for C₁₇ H₁₄ ClNO₄ : 61.54%C; 4.25%H; 4.22%N; Found:61.34%C; 4.15%H; 4.17%N

EXAMPLE 6

To a solution of 8.3 g ofethyl[7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetate, Example 5, in160 ml of ethyl alcohol is added 6 ml of 7N sodium hydroxide.Thereafter, the reaction mixture is refluxed for 45 minutes. Theprecipitate is collected by filtration and then successively rinsed withethyl alcohol and ether. The precipitate is suspended in 200 ml of hotwater and this mixture is acidified with concentrated hydrochloric acid.The acidified mixture is stirred for 1 hour and the gray precipitate iscollected by filtration. The precipitate is recrystallized from ethylacetate to yield the pure product[(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetic acid having amelting point of 219° to 221° C.

Analysis: Calculated for C₁₅ H₁₀ ClNO₄ : 59.32%C; 3.32%H; 4.61%N; Found:59.33%C; 3.38%H; 4.57%N

EXAMPLE 7

19.8 g of 3,2-dichloro-4-hydroxyphenyl-2'-furylmethanone oxime isdissolved in 200 ml of dimethylformamide, then 4.8 g of sodium hydrideis added thereto. After hydrogen gas evolution ceases the reactionmixture is heated at 130° C. The mixture is cooled to 5° C. and to thecooled mixture is added a solution of 16.7 g of bromoacetate in 20 ml ofdimethylformamide. After stirring for 45 minutes the reaction mixture isthen poured into water to produce a crystalline product. The product iscollected by filtration, sucessively washed with ethyl alcohol and etherand finally recrystallized from an ethyl alcohol-ethyl acetate mixtureto yield the productethyl[(7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl)oxy]acetate having amelting point of 151° to 152° C.

Analysis: Calculated for C₁₅ H₁₂ ClNO₅ : 56.00%C; 3.76%H; 4.35%N; Found:55.91%C; 3.83%H; 4.32%N

EXAMPLE 8

To a boiling suspension of 15.0 g ofethyl[(7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl)oxy]acetate, Example7, in 500 ml of boiling 95% ethyl alcohol there is added 10 ml of a 50%sodium hydroxide solution causing the sodium salt to precipitate outalmost immediately. An additional 300 ml of 95% ethyl alcohol is addedand boiling is maintained for 30 minutes. The reaction mixture ispermitted to cool slightly, after which 100 ml of a 5% hydrochloric acidsolution is added thereto. The product begins to separate with cooling,250 ml of water is added and the diluted mixture is chilled with ice.The precipitate is collected by filtration and recrystallized fromisopropyl alcohol to yield the product{[7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having amelting point of 230° to 233° C.

Analysis: Calculated for C₁₃ H₈ ClNO₅ : 53.17%C; 2.74%H; 4.77%N; Found:52.83%C; 2.83%H; 4.74%N

EXAMPLE 9

a. A mixture of 28.3 g of(2,3-dichloro-4-hydroxyphenyl)-(5'-methyl-2'-thienyl)methanone and 14.0g of hydroxylamine hydrochloride in 300 ml of pyridine is refluxed for16 hours. Thereafter, the solvent is removed under vacuum and theresidue is treated with 5% hydrochloric acid. The treated residue issuccessively extracted with a mixture of dichloroethane and ether anddried and the solvent removed by evaporation. The product is trituratedwith hexane to produce the desired oxime,(2,3-dichloro-4-hydroxyphenyl)-(5'-methyl-2'-thienyl)methanone oxime.

b. To a mixture of the above oxime in 200 ml of dimethylformamide thereis added 5.3 g of sodium hydride. The reaction mixture is maintained,successively, at 120° C. for 1.5 hours, 130° C. for 1 hour, and 140° C.for 1 hour, then cooled to 35° C. To this cooled mixture 18.3 g of theethyl bromoacetate in 20 ml of dimethylformamide there is added and themixture is stirred for 20 minutes. The reaction mixture is poured into asaturated sodium chloride solution to yield a crystalline product whichis collected by filtration. The product is washed successively withmethyl alcohol and ether and then recrystallized from isopropyl alcoholto give the productethyl{[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetatehaving a melting point of 149° to 150° C.

Analysis: Calculated for C₁₆ H₁₄ ClNO₄ S: 54.62%C; 4.04%H; 3.98%N;Found: 54.60%C; 3.97%H; 3.98%N

EXAMPLE 10

The substitution of(2,3-dichloro-4-hydroxyphenyl)-(5'-methyl-2'-furyl)methanone for(2,3-dichloro-4-hydroxyphenyl)-(5'-methyl-2'-thienyl)methanone in theprocedure described in Example 9(a) and, thereafter following theprocedure described in Example 9(b) providesethyl{[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetate,having a melting point of 139° to 141° C.

Analysis: Calculated for C₁₆ H₁₄ ClNO₅ : 57.23%C; 4.20%H; 4.17%N; Found:57.28%C; 4.18%H; 3.93%N

EXAMPLE 11

To a suspension of 15.0 g ofethyl[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl]oxy acetate,Example 10, in 800 ml of ethyl alcohol there is added 10 ml of a 50%sodium hydroxide solution. The reaction mixture is refluxed withvigorous stirring for 1.5 hours and 100 ml of 5% hydrochloric acid isadded thereto. The resulting solution is sequentially chilled anddiluted with water as the product begins to crystallize. The product iscollected by filtration and recrystallized from methyl alcohol to yield{[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid,mp 217°-219° C.

Analysis: Calculated for C₁₄ H₁₀ ClNO: 54.65%C; 3.28%H; 4.55%N; Found:54.74%C; 3.40%H; 4.49%N

EXAMPLE 12

a. A mixture of 2,3-dichloro-4-hydroxy-4'-methylbenzophenone and 12.5 gof hydroxylamine hydrochloride in 200 ml of pyridine is refluxed for 2hours. Thereafter the pyridine is evaporated off under vacuum and theresidue is partitioned between ethyl acetate and 5% hydrochloric acid.The ethyl acetate extract is, successively, washed with water, dried andconcentrated to dryness leaving2,3-dichloro-4-hydroxy-4'-methylbenzophenone oxime.

b. A mixture of the above oxime and 5.2 g of sodium hydride in 300 ml ofdimethylformamide is maintained at 87° C. for 3 hours. This mixture ispermitted to cool to ambient temperature, after which 16.0 g of ethylbromoacetate in 50 ml of dimethylformamide is added thereto dropwise.After addition is complete the mixture is stirred for 30 minutes andpoured into water to produce a precipitate which isethyl{[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp157°-159° C.

EXAMPLE 13

A mixture of 20 g ofethyl{[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetate, Example12, and 15 ml of 50% sodium hydroxide in 600 ml of ethyl alcohol isrefluxed for 1 hour. Thereafter, the hot mixture is diluted with 500 mlof water and acidified with concentrated hydrochloric acid. Theacidified suspension is, successively, stirred for 30 minutes andfiltered and the filter cake is recrystallized from dimethylformamide toyield the product{[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having amelting point of 257° to 260° C.

Analysis: Calculated for C₁₇ H₁₄ ClNO₄ : 60.48%C; 3.78%H; 4.41%N; Found:60.39%C; 3.77%H; 4.38%N

EXAMPLE 14

a. A mixture of 41 g of(2,3-dichloro-4-hydroxyphenyl)-4'-chlorobenzophenone and 18.9 g ofhydroxylamine hydrochloride in 300 ml of pyridine is refluxed for 2hours. Thereafter, the pyridine is removed under vacuum and the residueis partitioned between ethyl acetate and 5% hydrochloric acid. The ethylacetate portion is, successively, washed with water, dried andconcentrated to dryness leaving2,3-dichloro-4-hydroxy-4'-chlorobenzophenone oxime.

b. A mixture of the 41.5 g of the above oxime and 7.9 g of sodiumhydride in 300 ml of dimethylformamide is maintained at a temperataureof 111° C. for 2 hours. Thereafter, the reaction mixture is permitted tocool to ambient temperature after which a mixture of 23 g of ethylbromoacetate in 50 ml of dimethylformami is added thereto dropwise.After addition is complete the reaction mixture is stirred for 30minutes and permitted to stand for 16 hours. The mixture is poured intowater to yield a precipitate, collected by filtration, ofethyl{[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate,m.p. 179° C.

EXAMPLE 15

A mixture of 25 g ofethyl{[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate,Example 14, and 20 ml of 50% The hot mixture is diluted with 300 ml ofwater and then acidified with concentrated hydrochloric acid. Theacidified mixture is stirred for 30 minutes and then filtered and thefilter cake is recrystallized from a dimethylformamide-ethylacetatemixture to yield the product{[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acidhaving a melting point of 254° to 257° C.

Analysis: Calculated for C₁₅ H₉ Cl₂ NO₄ : 53.28%C; 2.68%H; 4.14%N;Found: 53.01%C; 2.39%H; 4.03%N

In the above examples, where not specifically shown, the oxime precursoris prepared from the appropriate ketone in a fashion similar to Example1c.

EXAMPLE 16

A suspension of 0.72 g ofethyl{[7-chloro-3-(2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetate, Example4, and 10 ml of concentrated aqueous sodium hydroxide in 40 ml of ethylalcohol is refluxed for 1 hour. Thereafter, the ethyl alcohol is removedby evaporation in vacuo. The residual suspension is acidified withconcentrated hydrochloric acid and then stirred at ambient temperaturefor 30 minutes. The resulting crude product is collected by filtrationand then recrystallized from ethyl alcohol to provide the product, mp217°-220° C., of{[7-chloro-3-(2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.

Analysis: Calculated for C₁₃ H₈ ClNO₄ S: 50.41%C; 2.60%H; 4.52%N. Found:50.13%C; 2.47%H; 4.48%N.

EXAMPLE 17

a. A reaction mixture of 32.8 g of 3-methyl-2-thiophene carboxylic acidchloride and 35.4 g of 2,3-dichloroanisole and 26.7 g of aluminumchloride in 200 ml of carbon disulfide is refluxed for 40 hours beforebeing poured into ice-hydrochloric acid. The resulting crystallineproduct is collected by filtration and then sequentially washed withhexane and recrystallized from a toluene-hexane mixture to provide theproduct, mp 136°-138° C., of(2,3-dichloro-4-methoxy)(3-methyl-2-thienyl)methanone.

Analysis: Calculated for C₁₃ H₁₀ Cl₂ O₂ S: 51.48%C; 3.35%H; 10.65%S.Found: 51.81%C; 3.35%H; 10.85%S.

b. A mixture of 0.6 g of(2,3-dichloro-4-methoxy)(3-methyl-2-thienyl)methanone and NH₂ OH.HCl inpyridine is converted to its corresponding oxime. Thereafter, the oxime(mixture of isomers) (37.8 g) is dissolved in 70 ml of dimethylformamideand the solution added to a suspension of 3.3 g of sodium hydride in 100ml of dimethylformamide. After the reaction is completed it is pouredinto water. The pH of the aqueous mixture is adjusted to 6-7 with dilutehydrochloric acid. The resulting precipitate is collected by filtrationand then sequentially washed well with ether and recrystallized from atoluene-hexane mixture to provide the product, mp 154°-156° C.,7-chloro-3(3-methyl-2-thienyl)-6-1,2-benzisoxazole.

Analysis: Calculated for C₁₃ H₁₀ ClNO₂ S: 55.81%C; 3.60%H; 5.01%N;11.46%S. Found: 55.90%C; 3.54%H; 4.98%N; 11.22%S.

c. A mixture of 13.3 g of7-chloro-3-(3-methyl-2-thienyl)-6-methoxy-1,2-benzisoxazole and 25 g ofBBr₃ in CH₂ Cl₂ is refluxed about 18 hours and then poured into H₂ O andextracted with ether. The ether extract is dried and evaporated and thentriturated with hexane to yield7-chloro-6-hydroxy-3-(3-methyl-2-thienyl)-1,2-benzisoxalole, mp197°-198° C.

Analysis: Calculated for C₁₂ H₈ ClNO₂ S: 54.24%C; 3.03%H; 5.27%N. Found:54.22%C; 3.05%H; 5.08%N.

d. A mixture of 10.3 g of7-chloro-6-hydroxy-3-(3-methyl-2-thienyl)-1,2-benzisoxazole in 60 ml DMFis added to a suspension of NaH (1.1 g) in 40 ml DMF. Ethyl bromoacetate(6.7 g) is added thereto and the reaction mixture is heated to 50° C.for 30 minutes. 100 ml H₂ O and 25% aqueous NaOH is added and thereaction mixture is heated to 90° C. for three hours. The reactionmixture is then poured into H₂ O and acidified with concentratedhydrochloric acid. The acidified mixture is extracted with ether, water,washed and dried. Evaporation and recrystallization form an ethylacetate-hexane mixture which gives{7-chloro-3-(3-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.

Analysis: Calculated for C₁₄ H₁₀ ClNO₄ S: 51.93%C; 3.11%H; 4.33%N.Found: 51.93%C; 3.05%H; 4.28%N.

EXAMPLE 18

A mixture of 15.0 g ofethyl{[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazole-6-yl]oxy}acetateof Example 9b and 10 ml of 50% NaOH in 800 ml of ethanol is refluxed for30 minutes and then 100 ml of the 5% HCl is added, making the solutionhomogeneous. A product begins to crystallize as the solution cools andadditional water is added. The product is filtered off andrecrystallized form isopropanol giving{[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid,mp 235°-238° C.

Analysis: Calculated for C₁₄ H₁₀ ClNO₄ S: 51.93%C; 3.11%H; 4.33%N;9.91%S. Found: 51.69%C; 3.14%H; 4.20%N; 10.02%S.

EXAMPLE 19

3-Furoyl chloride (18.0 g) and 2,3-dichloro anisole (24.7 g) aredissolved in 125 ml of CS₂ and treated with AlCl₃ (18.7 g), first at 5°C. and then at room temperature. After five hours the reaction isquenched with ice/HCl and extracted with CH₂ Cl₂. Drying and evaporationgives a crystalline product that is triturated with hexane to yield4-(3-furoyl)-2,3-dichloroanisole, mp 118°-122° C.

A molten bath of pyridine HCl is prepared by adding 16 ml ofconcentrated HCl (0.186 mole) to 14.2 g of pyridine and heating themixture to 210° C. under nitrogen and allowing the H₂ O to distill out.The anisole (5.0 g) is added in portions and heating is continued forone hour and the solution poured over ice and extracted with ethylacetate. Drying and evaporation gives 4-(3-furoyl)-2,3-dichlorophenol,mp 138°-142° C.

The phenol is combined with hydroxylamine hydrochloride in pyridine andrefluxed for three hours. The pyridine is evaporated off and theresultant mixture is acidified with hydrochloric acid and then extractedwith ethyl acetate. The ethyl acetate extract is water washed, dried andevaporated to dryness to yield an oxime which is dissolved in 100 ml ofDMF and added to a suspension of NaH (7.0 g) in 100 ml of DMF. Afterwarming for two hours at 120° C., the reaction is cooled to 45° C. andethyl bromoacetate (24.0 g) in 20 ml of DMF is added. The reaction isquenched with brine and a resultant solid product filtered and washedwith ethanol and then ether to give a crude phenoxy ester. Hydrolysis ofthe crude ester for 45 minutes in refluxing ethanol (500 ml) containing10 ml of 50% NaOH gives a crystalline acid after acidifying andchilling. The acid is recrystallized by suspending it in boilingmethanol and adding DMF until dissolution occurs. Water is then addedand crystallization begins immediately to yield{[7-chloro-3-(3-furyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp225°-227° C.

Analysis: Calculated for C₁₃ H₈ ClNO₅ : 53.17%C; 2.74%H; 4.77%N. Found:53.36%C; 2.85%H; 4.71%N.

EXAMPLE 20

a. To a solution of 24.6 g of 2,6-difluorobenzoylchloride in 100 ml of1,2-dichloroethane, 18.5 g of AlCl₃ is added in portions over a 30minute period. A solution of 22.5 g of 2,3-dichloroanisole in 100 ml of1,2-dichloroethane is added thereto. The mixture is stirred for one hourand poured over 100 ml concentrated HCl and ice. The organic layer isseparated and the aqueous layer extracted with CHCl₃. The organicextract is washed with water, dried (Na₂ SO₄) and evaporated to give anoil which crystallizes from hexane to yield solid2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone which uponrecrystallization from ether has an mp 94°-96° C.

Analysis: Calculated for C₁₄ H₈ Cl₂ F₂ O₂ : 53.02%C; 2.54%H; 11.98%F.Found: 53.21%C; 2.50%H; 12.08%F.

b. A mixture of 50.5 g of2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone, 44.27 g ofhydroxylamine HCl in 200 ml of pyridine is refluxed for 48 hours. Thepyridine is evaporated in vacuo and the residue partitioned between 5%HCl and ethyl acetate. The extract is washed with water, dried over Na₂SO₄ and evaporated to give a mixture of isomers. An analytical sample of2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone oxime, mp 173°-189° C.is recrystallized from 95% ethanol:

Analysis: Calculated for C₁₄ H₉ Cl₂ F₂ NO₂ : 50.62%C; 2.73%H; 4.22%N.Found: 50.84%C; 2.68%H; 4.14%N.

c. To a mixture of 5 g of NaH in 200 ml of DMF, 48 g of2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone oxime in 250 ml of DMFis added dropwise in an atmosphere of N₂ while the temperature ismaintained at approximately 40° C. After the addition, the mixture isstirred 30 minutes and poured into ice water. A crude product, which isa mixture of isomers, is filtered off and chromatographed on silica gelwith CHCl₃ as eluant to yield7-chloro-3-(2,6-difluorophenyl)-6-methoxy-1,2-benzisoxazole which isrecrystallized from toluene for analysis, mp 175°-179° C.

Analysis: Calculated for C₁₄ H₈ ClF₂ NO₂ : 56.87%C; 2.73%H; 4.74%N.Found: 56.99%C; 2.64%H; 4.64%N.

d. A mixture of 10.8 g of7-chloro-3-(2,6-difluorophenyl)-6-methoxy-1,2-benzisoxazole and 40.3 gof pyridine HCl is heated at 200° C. for 1 hour and then poured intovigorously stirred ice water. A product of7-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole precipitatesand is filtered and dried. An analytical sample is recrystallized fromtoluene, mp 216°-220° C.

Analysis: Calculated for C₁₃ H₆ ClF₂ NO₂ : 55.43%C; 2.15%H; 4.97%N.Found: 55.59%C; 2.29%H; 4.96%N.

e. A mixture of 1.18 g of NaH and 9.2 g of7-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole in 15 ml ofDMF is stirred 1 hour. A solution of 6.06 g of ethyl bromoacetate in 40ml of DMF is added thereto dropwise and stirred for one half hour. Tenmilliliters of 50% NaOH is added and the reaction mixture is warmed to80° C. for 1 hour. Concentrated HCl is added to the warm solution untilacidic. Water is added and{7-chloro-3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acidprecipitates which is filtered, dried and recrystallized fromtoluene-acetonitrile to give a product having a melting point of170°-172° C.

Analysis: Calculated for C₁₅ H₈ ClF₂ NO₄ : 53.04%C; 2.37%H; 4.12%N.Found: 53.17%C; 2.38%H; 4.18%N.

EXAMPLE 21

a. A mixture of 20.36 g of α-fluorocinnamoyl chloride and 14.4 g ofAlCl₃ in 100 ml of 1,2-dichloroethane is stirred 1 hour followed by thedropwise addition of 17.7 g of 2,3-dichloroanisole in 100 ml of1,2-dichloroethane. The reaction mixture is warmed to approximately 80°C. for 1 hour and poured over 100 ml of concentrated HCl and ice. Theaqueous layer is extracted with CHCl₃ and the combined organic layerwashed with water, dried over Na₂ SO₄ and evaporated to a solid residue.The residue is triturated with hexane to give4-(trans-α-fluorocinnamoyl)-2,3-dichloroanisole. A sample isrecrystallized from toluene, mp 137°-138° C.

Analysis: Calculated for C₁₆ H₁₁ Cl₂ FO₂ : 59.10%C; 3.41%H; 5.84%F.Found: 59.38%C; 3.46%H; 5.86%F.

b. A mixture of 26.6 g of4-(trans-α-fluorocinnamoyl)-2,3-dichloroanisole and 22.7 g ofhydroxylamine HCl is refluxed 18 hours. The pyridine is evaporated invacuo and the residue triturated with 5% HCl. A product is filtered off,dried and rinsed with ether-hexane giving a mixture of isomers. A sampleof 4-(trans-α-fluorocinnamoyl)-2,3-dichloroanisole oxime isrecrystallized from ethanol, mp 222°-238° C.

Analysis: Calculated for C₁₆ H₁₂ Cl₂ FNO₂ : 56.49%C; 3.56%H; 4.12%N.Found: 56.47%C; 3.51%H; 4.02%N.

c. A mixture of 0.43 g of NaH and 4 g of4-trans-α-fluorocinnamoyl)-2,3-dichloroanisole oxime in 60 ml of DMF isstirred for one half hour and poured into ice water. A precipitate whichformed is filtered and dried giving7-chloro-3-(trans-β-fluorostyryl)-6-methoxy-1,2-benzisoxazole.Recrystallization from toluene gives a pure product, mp 155°-161° C.

Analysis: Calculated for C₁₆ H₁₁ ClFNO₂ : 63.27%C; 3.65%H; 4.61%N.Found: 63.18%C; 3.42%H; 4.65%N.

d. A mixture of 1.4 g of7-chloro-3-(trans-β-fluorostyryl)-6-methoxy-1,2-benzisoxazole and 5.6 gof pyridine HCl is heated at 200° C. for 1 hour and then poured intovigorously stirring ice water. A product of7-chloro-3-(trans-β-fluorostyryl)-6-hydroxy-1,2-benzisoxazoleprecipitates and is filtered and dried, mp 226°-229° C.

Analysis: Calculated for C₁₅ H₉ ClFNO₂ : 62.19%C; 3.13%H; 4.84%N. Found:62.43%C; 3.17%H; 4.92%N.

e. To a mixture of 0.84 g of NaH in 100 ml of DMF, 6.77 g of7-chloro-3-(trans-β-fluorostyryl)-6-hydroxy-1,2-benzisoxazole in 50 mlof DMF is added dropwise in an atmosphere of N₂. The mixture is stirred1 hour and then 4.2 g of ethyl bromoacetate is added dropwise thereto.The reaction mixture is stirred for one half hour and fifteenmilliliters of 50% NaOH is added and the reaction mixture warmed to 80°C. for 1 hour. The reaction mixture is made acidic with concentrated HCland a product precipitates by the addition of water. The crude productis filtered, dried and recrystallized from 95% ethanol giving7-chloro-3-(trans-β-fluorostyryl)-1,2-benzisoxazol-6-yl]oxy acetic acid,mp 200°-203° C.

Analysis: Calculated for C₁₇ H₁₁ ClFNO₄ : 58.72%C; 3.18%H; 4.03%N.Found: 59.03%C; 3.29%H; 4.01%N.

EXAMPLE 22

a. To a solution of 52.23 g of 2,4-difluorobenzoylchloride in 200 ml of1,2-dichloroethane, 40 g of AlCl₃ is added over a 30 minute period. Asolution of 48.3 g of 2,3-dichloroanisole in 100 ml 1,2-dichloroethaneis added dropwise. There is a slow evolution of gas and the temperaturerises to approximately 30° C. The reaction mixture is warmed to 43° C.and the gas continues to evolve for approximately 30 minutes. Themixture is poured over concentrated HCl and ice. The organic layer isseparated and the aqueous layer is extracted two times with CHCl₃. Thecombined organic layers are washed with water, dried (Na₂ SO₄) andevaporated to give an oil. Trituration with hexane yields2,3-dichloro-4-methoxy-2',4'-difluorobenzophenone which isrecrystallized from ether, mp 139°-141° C.

Analysis: Calculated for C₁₄ H₈ Cl₂ F₂ O₂ : 53.02%C; 2.54%H; 11.98%N.Found: 53.09%C; 2.43%H; 11.84%N.

b. To 67 g of 2,3-dichloro-4-methoxy-2',4'-difluorobenzophenone in 300ml of pyridine is added 58 g of hydroxylamine HCl and the resultantmixture is refluxed for 18 hours. The pyridine is evaporated in vacuoand the residue is partitioned between 5% HCl and ethyl acetate. Theethylacetate extract is washed with water, dried over Na₂ SO₄ andevaporated to give 2,3-dichloro-4-methoxy-2',6'-difluorobenzophenoneoxime as a mixture of isomers. A sample is recrystallized from 95%ethanol, mp 180°-186° C.

Analysis: Calculated for C₁₄ H₉ Cl₂ F₂ NO₂ : 50.62%C; 2.73%H; 4.22%N.Found: 50.63%C; 2.80%H; 4.55%N.

c. To a mixture of 5.7 g of NaH in 100 ml of DMF, a solution of 53 g of2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone oxime in 250 ml of DMFis added dropwise maintaining the temperature at approximately 30° C.After the mixture is stirred for one and one half hours, a product isprecipitated by the addition of water. The crude product, which is amixture of isomers, is chromatographed on silica gel with toluene-hexaneas eluant to obtain a pure product of7-chloro-3-(2,4-difluorophenyl)-6-methoxy-1,2-benzisoxazole which isrecrystallized from toluene, mp 189°-191° C.

Analysis: Calculated for C₁₄ H₈ ClF₂ NO₂ : 56.87%C; 2.73%H; 4.74%N.Found: 56.94%C; 2.77%H; 4.66%N.

d. A solid mixture of 7.1 g of7-chloro-3-(2,4-difluorophenyl)-6-methoxy-1,2-benzisoxazole and 27.8 gof pyridine HCl is heated at 200° C. for one hour and the mixture pouredinto vigorously stirred ice water to precipitate a product. The productis filtered and dried giving7-chloro-3-(2,4-difluorophenyl)-6-hydroxy-1,2-benzisoxazole which isrecrystallized from toluene, mp 186°-190° C.

Analysis: Calculated for C₁₃ H₆ ClF₂ NO₂ : 55.43%C; 2.15%H; 4.97%N.Found: 55.68%C; 2.16%H; 4.92%N.

e. To a mixture of 0.86 g of NaH in 100 ml of DMF, under N₂, a solutionof 6.9 g of 7-chloro-3-(2,4-difluorophenyl)-6-hydroxy-1,2-benzisoxazolein 50 ml of DMF is added dropwise followed by the addition of 4.41 g ofethyl bromoacetate in 25 ml of DMF. The mixture is stirred for one halfhour and fifteen milliliters of 50% NaOH is added and the mixture warmedfor 1 hour at 80°-85° C. Concentrated HCl is then added until themixture is acidic.{[7-chloro-3-(2,4-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acidis precipitated by the addition of water and recrystallized fromtoluene-acetonitrile, mp 200°-203° C.

Analysis: Calculated for C₁₅ H₈ ClF₂ NO₄ : 53.04%C; 2.37%H; 4.12%N.Found: 53.24%C; 2.55%H; 4.39%N.

EXAMPLE 23

a. Dimethylsulfate (94.64 g) is added dropwise over a 40 minute periodto a cooled stirred solution of 2,5-dichlorophenol (122.25 g) and sodiumhydroxide (31.5 g) in water (300 ml). This mixture is stirred at roomtemperature for one hour, then at reflux for 2 hours, then cooled toroom temperature. The organic layer is separated and combined with etherextracts of the remaining aqueous layer. The ether solution is dried(saturated NaCl, Na₂ SO₄, K₂ CO₃) and the ether removed to give2,5-dichloroanisole. Distillation gives a colorless liquid (115° C. ataspirator vacuum).

A solution of o-fluorobenzoyl chloride (69.76) in carbon disulfide (25ml) is added at room temperature to a suspension of aluminum chloride(58.67 g) in carbon disulfide (450 ml) followed by the addition at roomtemperature of 70.81 g of 2,5-dichloroanisole in carbon disulfide (25ml). The mixture is stirred 4 hours at room temperature, during whichtime a precipitate forms. The mixture is then refluxed for one hour,cooled, and 58 g of AlCl₃ is added. The resultant mixture is thenrefluxed for 2 hours and stirred at room temperature for 18 hours. Themixture is poured over ice/HCl and extracted with methylene dichlorideto give an oil. Trituration with hexane-ether gives a solid.Recrystallization from diisopropyl ether gives a solid, meltingpartially at about 94° C. then at about 120° C. The solid remainingafter removal of the solvent from the filtrate is treated withether-petroleum ether to give 2,5-dichloro-4-(2-fluorobenzoyl)anisoleand recrystallization from methanol gives mp 100°-103° C.

Analysis: Calculated for C₁₄ H₉ Cl₂ FO₂ : 56.21%C; 3.04%H. Found:56.26%C; 3.00%H.

b. A mixture of 2,5-dichloro-4-(2-fluorobenzoyl)anisole (3 g) andhydroxylamine hydrochloride (1.4 g) in pyridine (25 ml) is refluxed forseveral hours until no ketone remains. The pyridine is removed underhigh vacuum and the residue diluted with water, then extracted withchloroform. The chloroform solution is dried and the chloroform removedto give a solid which is recrystallized from ether to afford(z)-2'-fluoro-2,5-dichloro-4-methoxybenzophenone oxime, mp 188° C.

Analysis: Calculated for C₁₄ H₁₀ Cl₂ FNO₂ : 53.52%C; 3.21%H; 4.46%N.Found: 53.44%C; 3.22%H; 4.36%N.

c. A solution of (z)-2'-fluoro-2,5-dichloro-4-methoxybenzophenone oxime(3.14 g) in DMF (20 ml) is added dropwise to a stirred suspension ofsodium hydride (0.6 g) in DMF (20 ml). The mixture is stirred 18 hoursat room temperature, then poured into ice/water and extracted withchloroform. The chloroform solution is washed with water, saturatedsodium chloride and dried over Na₂ SO₄ --MgSO₄. Removal of thechloroform gives a residue that on treatment with ether-petroleum ethergives a solid, mp 165°-166° C. Removal of the solvent from the filtrateyields a solid that on treatment with ether-petroleum ether gives5-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 165°-166° C.

Analysis: Calculated for C₁₄ H₉ ClFNO₂ : 60.55%C; 3.27%H; 5.04%H;12.77%Cl. Found: 60.71%C; 3.14%H; 4.99%N; 12.75%Cl.

d. A solution of 5-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole(1 g) and boron tribromide (1.3 l ml) in dichloroethane (30 ml) isrefluxed for about 24 hours. The reaction mixture is poured ontoice-water and extracted with dichloromethane to give a solid of5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 180°-182° C.

Analysis: Calculated for C₁₃ H₇ FClNO₂ : 59.22%C; 2.68%H; 5.31%N. Found:58.90%C; 2.68%H; 5.17%N.

e. A solution of 5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole(14.8 g) in DMF (40 ml) is added dropwise at room temperature to asuspension of sodium hydride (3.0 g) in DMF (40 ml) and the mixture isstirred at room temperature for one half hour. A solution of ethylbromoacetate (10.31 g) in DMF (40 ml) is then added dropwise and themixture stirred 18 hours at room temperature. An additional 0.3 g of NaHsuspended in DMF is added, followed by 1 g of ethyl bromoacetate. Themixture is warmed to 50° C. for 1 and one half hours, cooled and pouredover ice/water and extracted with ether. The ether extracts are washedwith water, saturated sodium chloride, dried over sodium sulfate and thesolvent is removed to give a solid. Trituration with ether-petroleumether (1:1) givesethyl{[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp114°-115° C.

Analysis: Calculated for C₁₇ H₁₃ ClFNO₄ : 58.37%C; 3.75%H; 4.00%N.Found: 58.15%C; 3.66%H; 3.93%N.

f. A mixture ofethyl{[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate (14g) sodium hydroxide (8 g), ethanol (500 ml) and water (300 ml) isrefluxed for five hours, cooled in an ice bath and acidified withconcentrated hydrochloric acid. The suspension is extracted withchloroform, the extract dried with saturated sodium chloride and thechloroform removed to give a solid, mp 214°-215° C. Recrystallizationfrom a 3:2 mixture of acetonitrile-toluene gives{[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.

Analysis: Calculated for C₁₅ H₉ ClFNO₄ : 56.00%C; 2.82%H; 4.35%N. Found:55.79%C; 2.69%H; 4.27%N.

EXAMPLE 24

a. To a solution of 57.6 g of 3,4-dichlorobenzoylchloride in1,2-dichloroethane (150 ml) is added 36.7 g of AlCl₃ in portions over a30 minute period. To the resultant mixture is added dropwise 44.26 g of2,3-dichloroanisole in 1,2-dichloroethane (150 ml). There is anevolution of gas and the reaction mixture is heated to 60° C. for onehour. The mixture is then poured over 150 ml of concentrated HCl and 150ml of ice and then extracted with CHCl₃ and then ethanol. The resultantorganic layer is washed with 10% aqueous K₂ CO₃, then water, dried over(Na₂ SO₄) and evaporated to yield2,3-dichloro-4-methoxy-3',4'-dichlorobenzophenone, mp 113°-140° C.

b. A mixture of 53 g of2,3-dichloro-4-methoxy-3',4'-dichlorobenzophenone and 40 g AlCl₃ in 400ml of benzene is refluxed for five hours and then cooled to roomtemperature and maintained there for about 18 hours. The mixture is thenpoured over 200 ml of concentrated HCl and 200 ml of ice and thenstirred at room temperature for one half hour. Ethylacetate is added tothe mixture and the ethyl acetate/benzene layer is washed with water,dried over Na₂ SO₄ and then evaporated to yield2,3-dichloro-4-hydroxy-3',4'-dichlorobenzophenone, mp 179°-180° C.

c. A mixture of 35.43 g of2,3-dichloro-4-hydroxy-3',4'-di-chlorobenzophenone, and 15.29 g ofhydroxylamine HCl in 300 ml of pyridine is refluxed for 2 hours. Thepyridine is evaporated in vacuo. The residue partitioned betweenethylacetate and 5% HCl. The extract is washed with water, dried overNa₂ SO₄ and evaporated to give the corresponding oxime.

To a solution of 35 g of the oxime in 300 ml of DMF, 6.0 g of NaH isadded and the mixture heated to an internal temperature of 103° C. forone hour 45 minutes followed by 100° C. internal temperature for threefourths of an hour. The reaction mixture is cooled to room temperatureand a solution of 18.37 g of ethyl bromoacetate in 50 ml of DMF is addeddropwise. The mixture is stirred for about 64 hours, poured over waterand the precipitate which forms is filtered off and rinsed with hexane.A crude product is recrystallized from ethanol to giveethyl{[7-chloro-3-(3,4-dichlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate,mp 123°-125° C.

To a suspension of 19 g of the ester in 400 ml of ethanol, 20 ml of 50%NaOH is added. A precipitate forms and the heterogeneous mixture isrefluxed for 1 hour. To the hot mixture 400 ml of water is addedfollowed by concentrated HCl until the mixture is acidic. The suspensionis stirred one half hour, filtered and recrystallized fromDMF-ethylacetate to give{[7-chloro-3-(3,4-dichlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid,mp 222°-224° C.

Analysis: Calculated for C₁₅ H₈ Cl₃ NO₄ : 48.35%C; 2.16%H; 3.76%N.Found: 58.40%C; 2.03%H; 3.93%N.

EXAMPLE 25

a. The Friedel-Crafts procedure of Example 24a is repeated with 48.13 gof o-chlorobenzoyl chloride being combined with 36.7 g AlCl₃ and 44.26 gof 2,3-dichloroanisole to yield a white crystalline product of2,3-dichloro-4-methoxy-2'-chlorobenzophenone, mp 117°-120° C.

b. The procedure of Example 24b is repeated except that 68 g of2,3-dichloro-4-methoxy-2'-chlorobenzophenone is combined with 58.6 g ofAlCl₃ in 500 ml of benzene. The resultant product is recrystallized fromtoluene to yield 2,3-dichloro-4-hydroxy-2'-chlorobenzophenone, mp74°-77° C.

c. To a solution of 53 g of 2,3-dichloro-4-hydroxy-2'-chlorobenzophenonein 350 ml of pyridine, 25.02 g of hydroxylamine HCl is added. Themixture is refluxed 2 hours. The pyridine is evaporated in vacuo, theresidue partioned between ethyl acetate and 5% HCl. The ethyl acetateextract is washed with water, dried over Na₂ SO₄ and evaporated to givethe corresponding oxime. To a solution of 49 g of the oxime in 300 ml ofDMF, 9.12 g of NaH is added and the mixture heated to an internaltemperature of 80°-84° C. for 1 hour. The reaction mixture is cooled toroom temperature and a solution of 27.5 g of ethyl bromoacetate in 50 mlof DMF is added dropwise. The mixture is stirred one half hour and wateradded to decompose excess NaH. The product is extracted with ethylacetate. The ethyl acetate extract is washed with 10% NaOH and water,dried over Na₂ SO₄ and evaporated to give a mixture. Chromatography ofthe mixture on silica gel with CHCl₃ as eluant yieldsethyl{[7-chloro-3-(2-chlorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetate.

To a solution of 5.86 g of the ester in 200 ml of hot ethanol, 6 ml of50% NaOH is added. A precipitate forms and the suspension is refluxedfor one hour. Two hundred milliliters of water are added to the mixtureand enough concentrated HCl to make the mixture acidic. The mixture isand enough concentrated HCl to make the mixture acidic. The mixture isstirred 18 hours at room temperature. A solid product precipitates outand is filtered and recrystallized from toluene giving{[7-chloro-3-(2-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp165°-168° C.

Analysis: Calculated for C₁₅ H₉ Cl₂ NO₄ : 53.28%C; 2.68%C; 2.68%H;4.14%N. Found: 53.50%C; 2.67%H; 3.95%N.

EXAMPLE 26

a. The Friedel-Crafts procedure of Example 24a is repeated with 35.4 gof 2,3-dichloroanisole, 32.4 g of o-toluoyl chloride and 28 g of AlCl₃being combined in 125 ml of 1,2-dichloroethane to yield a product of2,3-dichloro-4-methoxy-2'-methylbenzophenone.

b. The procedure of Example 24b is repeated except that 38 g of2,3-dichloro-4-methoxy-2'-methylbenzophenone is combined with 34.6 g ofAlCl₃ in 300 ml of benzene. The resultant product is recrystallized fromtoluene to yield 2,3-dichloro-4-hydroxy-2'-methylbenzophenone.

c. To a solution of 28 g of 2,3-dichloro-4-hydroxy-2'-methylbenzophenonein 250 ml of pyridine, 13.9 g of hydroxylamine HCl is added and themixture is refluxed 48 hours. The pyridine is evaporated in vacuo andthe residue is partitioned between ethyl acetate and 5% HCl. Theethylacetate extract is washed with water, dried over Na₂ SO₄ andevaporated to give the corresponding oxime. To a solution of 12 g of theoxime in 50 ml of DMF and 50 ml of toluene, 2.43 g of NaH is added. Themixture is heated under N₂ to an internal temperature of 95°-98° C. for5 and one quarter hours. An additional 50 ml of DMF is added and theinternal temperature held at 95° C. for another two hours. The reactionmixture is cooled to 30° C. and 7.5 g of ethyl bromoacetate is addeddropwise. After addition is complete the mixture is stirred one hour.Water is added and the product extracted ethylacetate, dried over Na₂SO₄ and evaporated to giveethyl[7-chloro-3-(2-tolyl)-1,2-benzisoxazol-6-yl]oxy acetate.

To a solution of 13.95 g of the ester in 500 ml of hot ethanol, 13 ml of50% NaOH is added. A precipitate forms and the suspension is refluxedone and one half hours. Five hundred milliliters of water is addedfollowed by the addition of concentrated HCl until the mixture isacidic. A solid product precipitates on cooling and the product isfiltered off and recrystallized from toluene giving{[7-chloro-3-(2-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp179°-181° C.

Analysis: Calculated for C₁₆ H₁₂ ClNO₄ : 60.48%C; 3.81%H; 4.41%N. Found:60.76%C; 3.91%H; 4.26%N.

EXAMPLE 27

a. The Friedel-Crafts procedure of Example 24a is repeated with 33.7 gof 2,3-dimethylbenzoyl chloride, 54 g of 2,3-dichloroanisole and 26.7AlCl₃ being reacted to form2,3-dichloro-4-methoxy-2',3'-dimethylbenzophenone.

b. The procedure of Example 24b is repeated with 39 g of2,3-dichloro-4-methoxy-2',3'-dimethylbenzophenone in 300 ml of benzene.The resultant product is recrystallized from toluene to yield2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone.

c. A mixture of 31 g of2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone and 30.5 g ofhydroxylamine hydrochloride in 250 ml of pyridine is refluxed for aboutone week. The pyridine is evaporated in vacuo and the residue ispartitioned between ethyl acetate and 5% HCl. The ethylacetate extractis washed, dried over Na₂ SO₄ and evaporated. Trituration with hexanegives 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime.

d. To a solution of 5 g of2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime in 70 ml of DMF,0.96 g of NaH is added. The internal temperature is held between95°-120° C. for seven hours, then the mixture is heated at 130° C. for1.5 hours. The reaction mixture is cooled and 2.94 g of ethylbromoacetate is added dropwise. The mixture is stirred one hour andwater is added dropwise. The product which forms is filtered off andrecrystallized from 95% ethanol to yieldethyl-{[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate,mp 89°-91° C.

Analysis: Calculated for C₁₉ H₁₈ ClNO₄ : 63.42%C; 5.04%H; 3.89%N. Found:63.25%C; 5.02%H; 3.79%N.

e. A suspension of 2 g ofethyl{[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate,50 ml of ethanol and 5 ml of 50% NaOH is refluxed 1 hour. To the hotmixture 50 ml of water is added enough concentrated HCl to make thereaction mixture acidic. Upon cooling and adding water,{[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acidis precipitated, mp 170°-172° C.

Analysis: Calculated for C₁₇ H₁₄ ClNO₄ : 61.54%C; 4.25%H; 4.22%N. Found:61.65%C; 4.38%H; 4.01%N.

EXAMPLE 28

a. 29.3 g of 2-bromopyridine in 150 ml of dry THF is added to 75 ml of2.6M n-butyllithium that was chilled to -65° C.2,3-dichloro-4-methoxybenzaldehyde (38.0 g) is then added in 300 ml ofTHF and the reaction mixture allowed to come to room temperature. It ispoured into H₂ O and the crystalline product filtered off, washed withether and dried to giveα-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol, mp 174°-176° C.

b. α-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol (31.86 g) isdissolved in 600 ml of acetic acid and 100 ml of H₂ O. Chromic anhydride(11.0 g) is added portionwise over five minutes. After three hours thereaction mixture is poured into H₂ O and extracted with ether. Thecombined organic phase is washed well with 10% NaHCO₃, then brine anddried. Removal of the solvent under reduced pressure gives a crystallineproduct of (2,3-dichloro-4-methoxyphenyl)(2-pyridyl)methanone, mp104°-107° C.

Analysis: Calculated for C₁₃ H₉ Cl₂ NO₂ : 55.34%C; 3.21%H; 4.97%N.Found: 55.29%C; 3.26%H; 4.93%N.

c. (2,3-dichloro-4-methoxyphenyl)(2-pyridyl)methanone (32.0 g) isrefluxed for four hours in 300 ml of ethanol containing 30 g ofhydroxylamine hydrochloride. The reaction mixture is poured into H₂ O,made basic with NH₄ OH and extracted with ethyl acetate. Drying andevaporation gives a crude oxime mixture ofE-(2-pyridyl)(2,3-dichloro-4-methoxyphenyl)methanone oxime andZ-(2-pyridyl)(2,3-dichloro-4-methoxyphenyl)methanone oxime.

The oxime mixture is dissolved in 200 ml of DMF and added to asuspension of 3.1 g NaH in 150 ml of DMF. After 15 minutes the reactionmixture is poured into H₂ O and the product filtered off. Onerecrystallization from isopropanol removes unreacted E-oxime, giving7-chloro-6-methoxy-3-(2-pyridyl)-1,2-benzisoxazole, mp 164°-166° C.

Analysis: Calculated for C₁₃ H₉ ClN₂ O₂ : 59.89%C; 3.48%H; 10.75%N.Found: 59.53%C; 3.37%H; 10.63%N.

d. 7-chloro-6-methoxy-3-(2-pyridyl)-1,2-benzisoxazole (24.4 g) isrefluxed for 1.5 hours in 450 ml of 48% HBr. The precipitatedhydrobromide salt is filtered off, washed with ether and neutralizedwith 10% NaHCO₃ solution. The free base is filtered off and dried,giving 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole, mp 209°-211°C.

Analysis: Calculated for C₁₂ H₇ ClN₂ O₂ : 58.43%C; 2.85%H; 11.36%N.Found: 58.16%C; 2.81%H; 11.42%N.

e. 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole (10.0 g) isdissolved in 80 ml of DMF and added to an ice cold suspension of NaH(1.1 g) in 50 ml of DMF. When hydrogen evolution ceases, ethylbromoacetate (7.5 g) in 20 ml of DMF is added. After an additional 90minutes, 200 ml of H₂ O and 10 ml of 50% NaOH are added and the reactionwarmed at 65° C. for 45 minutes. The mixture is poured into H₂ O,acidified to pH 1-2, and a solid product filtered and dried to give{[7-chloro-3-(2-pyridyl)-1,2-benzisoxazole-6-yl]oxy}acetic acid, mp255°-256° C.

Analysis: Calculated for C₁₄ H₉ ClN₂ O₄ : 55.18%C; 2.48%H; 9.20%N.Found: 55.35%C; 2.88%H; 9.45%N.

EXAMPLE 29

a. 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole, Example 28d, (9.9g) is dissolved in 600 ml of glacial acetic acid at 60° C.m-chloroperbenzoic acid (8.3 g of 85%) is then added portionwise. Afterwarming at 60° C. for a total of 14 hours the reaction mixture is pouredinto 2 l of H₂ O and the product filtered off and washed with methanol,then ether. Obtained in this manner is7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole 1'-oxide in the formof a hemihydrate after recrystallization from DMF/H₂ O, mp 214° C.

Analysis: Calculated for C₁₂ H₇ ClN₂ O₃.O.5H₂ O: 53.05%C; 2.97%H;10.31%N. Found: 53.14%C; 2.82%H; 10.47%N.

b. 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole 1'-oxide (7.30 g)is dissolved in 200 ml of DMF and added to a suspension of NaH (1.33 g)in 50 ml of DMF. After 15 minutes ethyl bromoacetate (5.0 g) in 20 ml ofDMF is added and the reaction is warmed at 50° C. for 10 hours. Thereaction mixture is quenched with H₂ O, acidified and the precipitatefiltered off and dried well. The precipitate is treated again with 1.33g of NaH and 5.0 g of ethyl bromoacetate in DMF. After 30 minutes 200 mlof H₂ O and 10 ml of 50% NaOH are added and the reaction mixture iswarmed at 50° C. for 30 minutes. It is then acidified and{[7-chloro-3-(2-pyridyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid 1'-oxideis obtained, mp 214° C. (d).

Analysis: Calculated for C₁₄ H₉ ClN₂ O₅ : 52.43%C; 2.83%H; 8.74%N.Found: 52.35%C; 2.79%H; 8.93%N.

EXAMPLE 30

a. m-dimethoxybenzene (27.6 g) and o-fluorobenzoyl chloride (31.7 g) aredissolved in 200 ml of dichloroethane and AlCl₃ (28.0 g) is addedportionwise. After two hours an additional 56 g of AlCl₃ is added andthe reaction mixture warmed at 60° C. for 1.5 hours. It is then pouredinto H₂ O and extracted with ethylacetate. Drying and evaporation givesa crystalline compound. Trituration with toluene gives2,4-dihydroxy-2'-fluorobenzophenone, mp 109°-111° C.

Analysis: Calculated for C₁₃ H₉ FO₃ : 67.24%C; 3.91%H; 8.18%F. Found:66.85%C; 3.75%H; 8.35%F.

b. 2,4-dihydroxy-2'-fluorobenzophenone (25.0 g) is refluxed 18 hours in250 ml of pyridine containing 17.1 g of hydroxylamine hydrochloride. Thereaction mixture is then partitioned between ether and 5% HCl and theorganic layer is separated. Drying and evaporation gives, aftercrystallization from toluene, one pure isomer of2,4-dihydroxy-2'-fluorobenzophenone [E-oxime], mp 170°-172° C.

Analysis: Calculated for C₁₃ H₁₀ FNO₃ : 63.16%C; 4.08%H; 5.67%N. Found:63.56%C; 4.28%H; 5.56%N.

c. The E-oxime 2,4-dihydro-2'-fluorobenzophenone oxime (18.6 g) iswarmed at 50° C. in 18.0 ml of acetic anhydride for 5 hours then at 60°C. for 6 hours. An additional 3.0 ml of acetic anhydride is added andthe reaction is allowed to remain undisturbed at room temperature forabout 73 hours. The crystalline product which separates from thereaction mixture is washed with cold ether to give a pure product ofE-4-acetoxy-2-hydroxy-2'-fluorobenzophenone O-acetyl oxime, mp 132°-134°C.

Analysis: Calculated for C₁₇ H₁₄ FNO₅ : 61.63%C; 4.26%H; 4.23%N. Found:61.80%C; 4.08%H; 4.07%N.

d. E-4-acetoxy-2-hydroxy-2'-fluorobenzophenone O-acetyloxime (18.4 g) isdissolved in 80 ml of DMF and added to an ice-cold suspension of NaH(3.3 g) in 100 ml of DMF. After 90 minutes the reaction mixture ispoured into H₂ O and a little insoluble precipitate is filtered off.Acidification of the aqueous filtrate and extraction with ether gives,after drying and evaporation,3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 206°-210° C.

Calculated for C₁₃ H₈ FNO₂ : 68.12%C; 3.52%H; 6.11%N. Found: 68.43%C;3.59%H; 6.14%N.

e. 3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (9.7 g) is dissolvedin 80 ml of DMF and added to an ice-cooled suspension of NaH (1.4 g) in50 ml of DMF. When hydrogen evolution stops, ethyl bromoacetate (7.5 g)in 20 ml of DMF is added and the reaction mixture is allowed to come toroom temperature. After two hours 200 ml of H₂ O and 10 ml of 50% NaOHare added and the reaction warmed at 50° C. After an additional 30minutes a product is collected after acidification and filtering.Recrystallization from toluene/CH₃ CN gives{[3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 182°-184°C.

Analysis: Calculated for C₁₅ H₁₀ FNO₄ : 62.72%C; 3.51%H; 4.88%N. Found:62.56%C; 3.61%H; 5.06%N.

EXAMPLE 31

a. The Friedel-Crafts procedure of Example 24a is repeated with 31.55 gof p-fluorobenzoyl chloride, 32 g of 2,3-dichloroanisole and 35.22 g ofAlCl₃ combined in 1,2-dichloroethane and reacted. The resultant crudeproduct is triturated with warm hexane, cooled and filtered to yield2,3-dichloro-4-methoxy-4'-fluorobenzophenone.

b. A mixture of 39.5 g of 2,3-dichloro-4-methoxy-4'-fluorobenzophenoneand 160 g of pyridine hydrochloride is heated at 200° C. for one hour.The reaction mixture is poured into ice water with stirring and aprecipitate forms. The precipitate is filtered and dried for about 18hours to yield 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone.

c. To a solution of 35 g of 2,3-dichloro-4-hydroxy-4'-fluorobenzophenonein 250 ml pyridine, 34.6 g of hydroxylamine HCl is added. The mixture isrefluxed for 4 hours. The pyridine is evaporated in vacuo. The residueis partitioned between 5% HCl and ethyl acetate. The ethyl acetateextract is washed with water, dried over Na₂ SO₄ and evaporated to give2,3-dichloro-4-hydroxy-4'-fluorobenzophenone oxime as a mixture ofisomers, mp 150°-156° C.

Analysis: Calculated for C₁₃ H₈ Cl₂ FNO₂ : 52.02%C; 2.69%H; 4.67%N.Found: 52.19%C; 2.74%H; 4.69%N.

d. To a mixture of 4.0 g NaH in 50 ml DMF, a solution of 20 g of2,3-dichloro-4-hydroxy-4'-fluorobenzophenone oxime in 100 ml of DMF isadded dropwise in an atmosphere of N₂. The reaction mixture is heated toan internal temperature of 96° C. for 2 hours. The reaction mixture iscooled to 40° C. and 12.3 g of ethyl bromoacetate is added dropwise andthe mixture is stirred for one hour. Twenty milliliters of 50% NaOH and100 ml of water is added and the reaction is heated at 80°-90° C. forone hour. Concentrated HCl is added until the reaction mixture is acidicand the mixture is stirred for one half hour and water added. A solidproduct is collected by filtration and recrystallized to give a pureproduct of{[7-chloro-3-(4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp233°-237° C.

Analysis: Calculated for C₁₅ H₉ ClFNO₄ : 56.00%C; 2.83%H; 4.36%N. Found:55.76%C; 2.90%H; 4.29%N.

EXAMPLE 32

a. 2,6-dimethoxytoluene (20.0 g) and o-fluorobenzoyl chloride (19.8 g)are dissolved in 250 ml of dichloroethane and chilled to 5° C. AlCl₃ isadded portionwise and when the addition is complete the reaction mixtureis allowed to warm to room temperature over 30 minutes, then refluxed 30minutes. It is then poured into 5% HCl and allowed to stand undisturbed18 hours. Extraction with ether, followed by drying and concentration,gives crystalline material that is washed with hexane to give2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone, mp 118°-120° C.

Analysis: Calculated for C₁₅ H₁₃ FO₃ : 69.22%C; 5.04%H; 7.30%F. Found:69.23%C; 5.01%H; 6.98%F.

b. 2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone (30.0 g) isrefluxed 18 hours in 350 ml of pyridine containing 32.0 g ofhydroxylamine hydrochloride. The solvent is removed in vacuo and theresidue is distributed between ether and 5% HCl. Drying andconcentration of the ether gives a crude product that is heated as amelt at 200° C. for 30 minutes in a nitrogen atmosphere. The melt isallowed to cool and the solid mass is triturated well with hexane togive E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime, mp167°-169° C.

Analysis: Calculated for C₁₅ H₁₄ FNO₃ : 65.44%C; 5.13%H; 5.09%N. Found:65.49%C; 5.26%H; 4.83%N.

c. E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime (20.0 g)is warmed on a steam bath for one hour with 12 ml of acetic anhydride.The acetic anhydride is evaporated in vacuo and the product isdistributed between ether and H₂ O, then the ether is washed with 10%NaHCO₃. Evaporation and trituration of the crystalline product withhexane gives E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenoneO-acetyl oxime, mp 83°-86° C.

Analysis: Calculated for C₁₂ H₁₆ FNO₄ : 64.34%C; 5.08%H; 4.42%N. Found:64.30%C; 5.08%H; 4.26%N.

d. E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone O-acetyl oxime(22.0 g) is dissolved in 100 ml of DMF and added to a suspension of 2.5g NaH in 100 ml DMF. An ice bath is applied to keep the reactiontemperature <30° C. After 40 minutes the reaction is poured into H₂ Oand extracted with ether. After washing well with H₂ O, the ether isdried and evaporated to give a crystalline product that is washed withcold hexane to give3-(2-fluorophenyl)-6-methoxy-7-methyl-1,2-benzisoxazole, mp 105°-108° C.

Analysis: Calculated for C₁₅ H₁₂ FNO₂ : 70.03%C; 4.70%H; 5.45%N. Found:69.96%C; 4.76%H; 3.36% N.

e. 3-(2-fluorophenyl)-6-methoxy-7-methyl-1,2-benzisoxazole (16.1 g) isheated at 200° C. for two hours with 64 g of pyridine hydrochloride. Themelt is poured into H₂ O and extracted with ethyl acetate. After washingwith 5% HCl the ethyl acetate is dried and evaporated to give3-(2-fluorophenyl)-6-hydroxy-7-methyl-1,2-benzisoxazole, mp 216°-219° C.

Analysis: Calculated for C₁₄ H₁₀ FNO₂ : 69.13%C; 4.14%H; 5.76%N. Found:68.91%C; 4.03%H; 5.82%N.

f. 3-(2-fluorophenyl)-6-hydroxy-7-methyl-1,2-benzisoxazole (10.6 g) isdissolved in 90 ml of DMF and treated with 8.0 g of ethyl bromoacetateand 6.7 g of K₂ CO₃. The reaction is warmed at 60° C. for 2 hours thenallowed to return to ambient. After 18 hours at ambient, water (200 ml)and 50% NaOH (15 ml) are added and the solution heated at 90° C. for 90minutes. The mixture is poured into H₂ O and acidified and then it isextracted into ether. Drying and evaporation gives crystalline productof {[3-(2-fluorophenyl)-7-methyl-1,2-benzisoxaol-6-yl]oxy}acetic acid,mp 158°-160° C.

Analysis: Calculated for C₁₆ H₁₂ FNO₄ : 63.78%C; 4.02%H; 4.65%N. Found:63.89%C; 4.06%H; 4.58%N.

EXAMPLE 33

a. m-chloroanisole (28.5 g) and o-fluorobenzoyl chloride (31.7 g) aredissolved in 200 ml of dichloroethane and treated at 10° C. with 26.7 gof AlCl₃. After 45 minutes the reaction mixture is poured over ice andextracted with ether. Drying and evaporation, followed by triturationwith hexane gives material that contains2-chloro-2'-fluoro-4-methoxybenzophenone. Recrystallization from Et₂O/hexane gives 2-chloro-2'-fluoro-4-methoxybenzophenone, mp 77°-79° C.

Analysis: Calculated for C₁₄ H₁₀ ClFO₂ : 63.53%C; 3.81%H; 7.18%F. Found:63.77%C; 3.75%H; 7.25%F.

b. 2-chloro-2'-fluoro-4-methoxybenzophenone (15.5 g) is refluxed forthree hours in 150 ml of pyridine containing 10.0 g of hydroxylaminehydrochloride. The pyridine is removed in vacuo and the residue isdistributed between ether and 5% HCl. Drying and evaporation of theorganic phase gives an isomeric mixture of oximes. The mixture isdissolved in 50 ml of DMF and is added to a suspension of 1.5 g NaH in30 ml of DMF. After warming at 60° C. for 30 minutes the reactionmixture is poured into H₂ O and extracted with ether. Concentrationunder reduced pressure gives a solid. Recrystallization from ether gives3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 101°-103° C.

Analysis: Calculated for C₁₄ H₁₀ FNO₂ : 69.13%C; 4.14%H; 5.76%N. Found:69.08%C; 4.29%H; 5.65%N.

c. 10 g of 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole are dissolvedin 400 ml of dry THF at -40° C. and treated with 21 ml of 2.2Mn-butyllithium. After stirring for one hour, I₂ (11.7 g) in 90 ml ofether is added. The reaction mixture is poured into Na₂ S₂ O₃, then H₂O. Drying and concentration gives3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxazole, mp 135°-138° C.

Analysis: Calculated for: C₁₄ H₉ FlNO₂ : 45.55%C; 2.46%H; 3.80%N;34.38%I. Found: 44.94%C; 2.43%H; 3.70%N; 34.09%I.

d. 3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxazole (8.2 g) isrefluxed 18 hours in 130 ml of CH₂ Cl₂ containing 6.6 ml of BBr₃. Thereaction mixture is poured into H₂ O and extracted into ether. Dryingand evaporation gives a crystalline product that is triturated well withhexane to yield 3-(2-fluorophenyl)-6-hydroxy-7-iodo-1,2-benzisoxazole,mp 212°-214° C.

Analysis: Calculated for C₁₃ H₇ FlNO₂ : 43.97%C; 1.99%H; 3.95%N;35.74%I. Found: 44.19%C; 2.00%H; 3.86%N; 35.12%I.

e. 3-(2-fluorophenyl)-6-hydroxy-7-iodo-1,2-benzisoxazole (7.80 g) in 80ml of DMF is treated at 60° C. with 6.6 g of K₂ CO₃ and 7.9 g of ethylbromoacetate. After one hour the temperature is increased to 90° C. and80 ml of H₂ O and 8 ml of 50% NaOH are added. After an additional 30minutes the mixture is poured into H₂ O and acidified and then extractedinto ether, dried and evaporated to yield{[3-(2-fluorophenyl)-7-iodo-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp178°-180° C.

Analysis: Calculated for C₁₅ H₉ FlNO₄ : 43.61%C; 2.20%H; 3.39%N. Found:43.25%C; 2.12%H; 3.28%N.

EXAMPLE 34

a. 10 g of 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole of Example 33bare dissolved in 400 ml of dry THF and treated at -40° C. with 21 ml of2.2M n-butyllithium. After stirring for one hour, bromine (2.5 ml) isadded dropwise. The reaction mixture is poured into H₂ O, extracted intoether and washed with Na₂ S₂ O₃ solution. Drying and evaporating gives amaterial that contains the desired brominated product,7-bromo-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 150°-153° C.

Analysis: Calculated for C₁₄ H₉ BrFNO₂ : 52.19%C; 2.82%H; 4.35%N;24.81%Br. Found: 51.97%C; 2.83%H; 4.28%N; 25.17%Br.

b. 7-bromo-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole (7.20 g) isrefluxed for 18 hours in 130 ml of CH₂ Cl₂ containing 6.6 ml of BBr₃.The reaction mixture is poured into H₂ O and extracted into ethylacetate. Evaporation and trituration with hexane gives the correspondingphenol, mp 231°-234° C.

The phenol (6.30 g) in 80 ml of DMF is treated at 60° C. with 6.6 g ofK₂ CO₃ and 7.9 g of ethyl bromoacetate. After one hour, 80 ml of H₂ Oand 8 ml of 50% NaOH are added and the temperature is raised to 90° C.After an additional 45 minutes the reaction is acidified and extractedinto ethylacetate. Evaporation and recrystallization from toluene/CH₂ CNgives {[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid, mp 180°-182° C.

Analysis: Calculated for C₁₅ H₉ BrFNO₄ : 49.20%C; 2.48%H; 3.83%N. Found:49.19%C; 2.47%H; 3.88%N.

EXAMPLE 35

a. To a mixture of 4 g of 2-chlororesorcinol dimethyl ether and 3.7 g of2,3-difluorobenzoyl chloride in 60 ml of 1,2-dichloroethane at 5° C.,3.06 g of AlCl₃ is added in portions. The mixture is allowed to warm toroom temperature and then refluxed for 30 minutes. The reaction mixtureis poured into concentrated HCl-ice and is permitted to stand about 72hours. The aqueous layer is extracted with additional organic solvent,dried over Na₂ SO₄ and evaporated to give3-chloro-2-hydroxy-4-methoxy-2',3'-difluorobenzophenone, mp 161°-162° C.

Analysis: Calculated for C₁₄ H₉ ClF₂ O₃ : 56.30%C; 3.04%H; 12.72%F.Found: 56.26%C; 3.06%H; 12.56%F.

b. To a solution of 24 g of3-chloro-2-hydroxy-4-methoxy-2',3'-difluorobenzophenone in 160 mlpyridine, 22 g of hydroxylamine HCl is added. The mixture is refluxedfor 2 hours and the pyridine evaporated in vacuo. The residue ispartitioned between ethyl acetate and 5% HCl. The ethyl acetate extractis washed with water, dried over Na₂ SO₄ and evaporated to give a paleyellow solid which consists of two isomers. The solid is melted at 205°C. for approximately 13 minutes. The residue is dissolved in hotethylacetate and then evaporated to dryness givingE-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone oxime, mp198°-199° C.

Analysis: Calculated for C₁₄ H₁₀ ClF₂ NO₃ : 53.60%C; 3.21%H; 4.47%N.Found: 53.95%C; 3.29%H; 4.42%N.

c. A mixture of 1.5 g ofE-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone oxime and 0.67g of acetic anhydride are warmed at 60° C. for 30 minutes. The mixtureis dissolved and then solidifies. The residue is partitioned betweenethyl acetate and 10% NaHCO₃. The ethyl acetate extract is washed, driedover Na₂ SO₄ and evaporated to giveE-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyloxime, mp 136°-139° C.

Analysis: Calculated for C₁₆ H₁₂ ClF₂ NO₄ : 54.02%C; 3.40%H; 3.94%N.Found: 53.89%C; 3.48%H; 3.97%N.

d. To a mixture of 1.4 g of NaH in 200 ml of DMF, a solution of 19 g ofE-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oximein 200 ml of DMF is added dropwise in an atmosphere of N₂. The mixtureis stirred for one half hour and then warmed at 45° C. for one halfhour. Water is added and a product precipitates and is filtered anddried giving7-chloro-3-(2,3-difluorophenyl)-6-methoxy-1,2-benzisoxazole, mp184°-189° C.

Analysis: Calculated for C₁₄ H₈ ClF₂ NO₂ : 56.87%C; 2.73%H; 4.47%N.Found: 56.95%C; 2.84%H; 4.77%N.

e. A solid mixture of 12.4 g of7-chloro-3-(2,3-difluorophenyl)-6-methoxy-1,2-benzisoxazole and 50 g ofpyridine HCl is heated to 200° C. for 45 minutes. The mixture is pouredinto vigorously stirred ice water and7-chloro-6-hydroxy-3-(2,3-difluorophenyl)-1,2-benzisoxazoleprecipitates, mp 250°-254° C.

Analysis: Calculated for C₁₃ H₆ ClF₂ NO₂ : 55.43%C; 2.15%H; 4.97%N.Found: 55.60%C; 2.25%H; 4.91%N.

f. To a solution of 12 g of7-chloro-6-hydroxy-3-(2,3-difluorophenyl)-1,2-benzisoxazole in 120 ml ofDMF, 6.36 g of K₂ CO₃ is added followed by 7.83 g of BrCH₂ CO₂ C₂ H₅.The reaction is warmed at 60° C. for two hours and then allowed to standfor 18 hours. To the mixture 200 ml of water and 15 ml of 50% NaOH areadded. The mixture is warmed at 90° C. for 90 minutes, poured into waterand acidified. The product is extracted into ethylacetate which is driedover Na₂ SO₄ and evaporated to give{[7-chloro-3-(2,3-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid,mp 183°-187° C.

Analysis: Calculated for C₁₅ H₈ ClF₂ NO₄ : 53.04%C; 2.37%H; 4.12%N.Found: 53.20%C; 2.49%H; 3.88%N.

EXAMPLE 36

a. To a solution of 10 g (0.033 m) of2'-fluoro-4-methoxy-2,3-dichlorobenzophenone of Example 1 a in 100 ml ofpyridine, 3.17 g of hydroxylamine HCl is added. The mixture is refluxedfor about 64 hours. The pyridine is evaporated and the residuepartitioned between 5% HCl and ethylacetate. The ethylacetate extract iswashed with water, dried over Na₂ SO₄ and evaporated to give2,3-chloro-4-methoxy-2'-fluorobenzophenone oxime mp 195°-197° C.

Analysis: Calculated for C₁₄ H₁₀ Cl₂ FNO₂ : 53.52%C; 3.21%H; 4.46%N.Found: 53.55%C; 3.10%H; 4.42%N.

b. To a solution of 8 g of 2,3-dichloro-4-methoxy-2'-fluorobenzophenoneoxime in 50 ml of DMF, 0.67 g of NaH is added under a N₂ atmosphere. Themixture is stirred for one hour and water is added to precipitate7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole which isfiltered and dried, mp 155°-158° C.

Analysis: Calculated for C₁₄ H₉ ClFNO₂ : 60.55%C; 3.26%H; 5.05%N. Found:60.63%C; 3.15%H; 5.01%N.

c. A solid mixture of 2 g of7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole and 20 g ofpyridine hydrochloride is heated at 190°-210° C. for one hour. The hotreaction mixture is poured into vigorously stirred ice water. Themixture is made slightly acidic.7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole is collected byfiltration and dried, mp 140°-141° C.

Analysis: Calculated for C₁₃ H₇ ClFNO₂ : 59.22%C; 2.68%H; 5.31%N. Found:59.16%C; 2.65%H; 5.23%N.

d. The procedure of Example 35f may be employed with7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole to yield{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, theproduct of Example 1d.

EXAMPLE 37

a. 2-chlororesorcinol dimethyl ether (22.0 g) and o-fluorobenzoylchloride (20.2 g) are dissolved in 250 ml of dichloroethane, chilled inan ice bath and treated with AlCl₃ (18.6 g). Fifteen minutes after theaddition is complete, the reaction is heated to reflux for 30 minutes.It is poured into H₂ O and extracted with ethylacetate. Evaporation andtrituration with hexane gives3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone, mp 132°-133° C.

Analysis: Calculated for C₁₄ H₁₀ ClFO₃ : 59.90%C; 3.59%H; 12.63%Cl.Found: 59.77%C; 3.59%H; 12.51%Cl.

b. 3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone (24.6 g) isrefluxed for 18 hours in 300 ml of pyridine containing 12.2 g ofhydroxylamine hydrochloride. The reaction mixture is concentrated underreduced pressure and is distributed between ether and 5% HCl. Theorganic phase is dried and evaporated and the resulting crystallineproduct fused at 205° C. for 45 minutes. The product is cooled andrecrystallized from toluene to giveE-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone oxime, mp 184°-186°C.

Analysis: Calculated for C₁₄ H₁₁ ClFNO₃ : 56.86%C; 3.75%H; 4.79%N.Found: 56.67%C; 3.68%H; 4.66%N.

c. E-3-chloro-2'-fluoro-2-hydroxy4-methoxybenzophenone oxime (18.1 g) iswarmed at 60° C. for 30 minutes with 9 ml of acetic anhydride. Thereaction mixture is distributed between ether and 10% NaHCO₃ and washedwith 10% NaHCO₃ until the washes remained basic. Drying, evaporation andtrituration with hexane givesE-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp125°-128° C.

Analysis: Calculated for C₁₆ H₁₃ ClFNO₄ : 56.90%C; 3.88%H; 4.15%N.Found: 59.79%C; 3.85%H; 4.20%N.

d. The procedure of Example 35d may be repeated to yield7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole. Thereafter theprocedures of Example 36c and d may be employed to yieldethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.

EXAMPLE 38

a. 5.0 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole ofExample 36c in 30 ml of DMF is added dropwise with stirring to 1.1 g NaHin 30 ml DMF. After one hour, 2.6 ml of ethyl-2-bromoproprionate isadded and the solution is stirred 1.5 hours. The solution is then pouredonto ice andethyl-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}propionateprecipitates which is filtered and dried, mp 79° C.

Analysis: Calculated for C₁₈ H₁₅ ClFNO₄ : 59.50%C; 4.13%H; 3.85%N;9.60%Cl. Found: 59.48%C; 4.09%H; 4.00%N; 9.58%Cl.

b. 6.8 g ofethyl-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}propionateis dissolved in 35 ml of methanol and 25 ml of a 15% NaOH solution isadded. The suspension is heated for two hours. The reaction mixture ispoured onto ice, acidified with HCl and a solid precipitates which isfiltered and dried in vacuo to give2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-3-yl]oxy}propionicacid, mp 159°-161° C.

Analysis: Calculated for C₁₆ H₁₁ ClFNO₄ : 57.2%C; 3.28%H; 4.18%N;10.55%Cl. Found: 56.8%C; 3.24%H; 4.17%N; 10.51%Cl.

EXAMPLE 39

a To a mixture of 21 g of 2,5-difluorobenzoyl chloride and 20.4 g of2-chlororesorcinol dimethyl ether in 250 ml of 1,2-dichloroethane at5°-10° C. 15.7 g of AlCl₃ is added in portions. The mixture is allowedto warm to room temperature and is then refluxed for 30 minutes. Themixture is poured into concentrated HCl and ice and stirred forapproximately one hour. The product is extracted with ethyl acetate,dried over Na₂ SO₄ and evaporated to give3-chloro-2',5'-dilfluoro-2-hydroxy-4-methoxybenzophenone, mp 178°-180°C.

Analysis: Calculated for C₁₄ H₉ ClF₂ O₃ : 56.30%C; 3.04%H; 12.72%N.Found: 56.16%C; 3.01%H; 12.75%N.

b. A mixture of 28 g of3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone and 26 g ofhydroxylamine HCl in 250 ml pyridine is refluxed for three hours.Pyridine is evaporated and the residue partitioned between ethyl acetateand 5% HCl. The ethyl acetate extract is washed with water, dried overNa₂ SO₄ and evaporated to give a solid product as a mixture of isomers.The solid is heated at 200°-210° C. for approximately 30-45 minutes andrecrystallized from toluene givingE-3-chloro-2',5'-difluro-2-hydroxy-4-methoxybenzophenone oxime, mp209°-210° C.

Analysis: Calculated for C₁₄ H₁₀ ClF₂ NO₃ : 53.60%C; 3.29%H; 4.47%N.Found: 53.61%C; 3.22%H; 4.43%N.

c. A mixture of 19 g ofE-3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone oxime and 10ml of acetic anhydride was warmed at 60° C. for 30 minutes. On coolingthe mixture solidifies. The residue is partitioned between ethyl acetateand 10%NaHCO₃. The ethylacetate extract is washed with water, dried overNa₂ SO₄ and evaporated to giveE-3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyloxime, mp 130°-131° C.

Analysis: Calculated for C₁₆ H₁₂ ClF₂ NO₄ : 54.02%C; 3.40%H; 3.94%N.Found: 53.76%C; 3.37%H; 3.89%N.

d. To a suspension of NaH/200 ml of DMF in an atmosphere of N₂, 19.5 gof E-3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyloxime in 50 ml of DMF is added dropwise. The mixture is stirred 30minutes and water is added to precipitate7-chloro-3-(2,5-difluorophenyl)-6-methoxy-1,2-benzisoxazole, mp198°-199° C.

Analysis: Calculated for C₁₄ H₈ ClF₂ NO₂ : 56.87%C; 2.73%H; 4.74%N.Found: 56.74%C; 2.70%H; 4.70%N.

e. A mixture of 10 g of7-chloro-3-(2,5-difluorophenyl)-6-methoxy-1,2-benzisoxazole and 40 g ofpyridine HCl is heated at 200° C. for 45 minutes. The hot mixture ispoured into vigorously stirred ice water and a product precipitates out.The product is filtered and dried giving7-chloro-3-(2,5-difluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp256°-257° C.

Analysis: Calculated for C₁₃ H₆ ClF₂ NO₂ : 55.43%C; 2.15%H; 4.97%N.Found: 55.26%C; 2.02%H; 4.93%N.

f. To a solution of 9.3 g of7-chloro-3-(2,5-difluorophenyl)-6-hydroxy-1,2-benzisoxazole in 100 ml ofDMF, 4.97 g of K₂ CO₃ and 6.07 g of ethyl bromoacetate is addeddropwise. The mixture is heated for two hours at 60° C. To the mixture200 ml of water and 15 ml of 50% NaOH are added. The mixture is stirredat 90° C. for 90 minutes and then poured into water and acidified. Theproduct is extracted with ethylacetate, dried over Na₂ SO₄ andevaporated to give{[7-chloro-3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.

Analysis: Calculated for C₁₅ H₈ ClF₂ NO₄ : 53.04%C; 2.37%H; 4.12%N.Found: 53.37%C; 2.39%H; 4.01%N.

EXAMPLE 40

a. 2-chlororesorcinol dimethyl ether (3.4 g) is dissolved in 20 ml ofCH₂ Cl₂ and TiCl₄ (4.3 ml) is added. To this solution is addeddichloromethyl methyl ether (2.3 g). After 30 minutes the reactionmixture is poured into H₂ O into H₂ O and extracted with ether. Dryingand evaporation gives 3-chloro-2,4-dimethoxybenzaldehyde, mp 107°-108°C.

Analysis: Calculated for C₉ H₉ ClO₃ : 53.88%C; 4.52%H; 17.68%Cl. Found:53.93%C; 4.52%H; 17.42%Cl.

b. 3-chloro-2,4-dimethoxybenzaldehyde (2.75 g) is refluxed for 30minutes in 20 ml of dichloroethane containing 1.8 g of AlCl₃. Thereaction mixture is then poured into H₂ O and extracted with CH₂ Cl₂.Evaporation and recrystallization from isopropanol gives3-chloro-2-hydroxy-4-methoxybenzaldehyde, mp 125° C.

Analysis: Calculated for C₈ H₇ ClO₃ : 51.49%C; 3.78%H; 19.00%Cl. Found:51.33%C; 3.78%H; 18.65%Cl.

c. 3-chloro-2-hydroxy-4-methoxybenzaldehyde (1.48 g) is suspended in 15ml of H₂ O and hydroxylamine-O-sulfonic acid (1.08 g) is added, alongwith 0.1 g of Na₂ SO₄. After three hours an additional 15 ml of H₂ O isadded. After a total of four hours the reaction mixture is treated with8% NaHCO₃ solution and then extracted into ether. Evaporation andtrituration with hexane gives a solid product. Recrystallization fromtoluene/hexane gives 7-chloro-6-methoxy-1,2-benzisoxazole, mp 115°-118°C.

Analysis: Calculated for C₈ H₆ ClNO₆ : 52.33%C; 3.29%H; 7.63%N. Found:52.35%C; 3.30%H; 7.71%N.

d. The procedure of Example 35e and f may be employed with7-chloro-6-methoxy-1,2-benzisoxazole to yield{[7-chloro-1,2-benzisoxazol-6-yl]oxy}acetic acid.

EXAMPLE 41

a. To a solution of 1.7 g of 2-chlororesorcinol dimethyl ether and 2.08g of o-trifluoromethyl benzoyl chloride in 50 ml of 1,2-dichloroethaneat 5°-7° C., 1.6 g of ferric chloride is added gradually. The mixture isbrought to room temperature and allowed to stand 18 hours. The reactionmixture is refluxed 30 minutes and poured into 5% HCl and ice. Theaqueous phase is extracted with additional organic solvent. The combinedorganic extracts are washed with water, dried over Na₂ SO₄ andevaporated to give3-chloro-2-hydroxy-4-methoxy-2'-trifluoromethylbenzophenone, mp101°-102° C.

Analysis: Calculated for C₁₅ H₁₀ ClF₃ O₃ : 54.48%C; 3.05%H; 17.24%F.Found: 54.16%C; 2.91%H; 17.16%F.

b. The procedures described in the foregoing examples (such as Example35) may be employed with3-chloro-2-hydroxy-4-methoxy-2'-trifluoromethylbenzophenone to obtainthe corresponding oxime, cyclizing the oxime and forming the acid toyield{[7-chloro-3-(2-trifluoromethylphenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid.

EXAMPLE 42

a. 10 g of 7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole ofExample 36b is dissolved in glacial acetic acid (800 ml) with stirringand chlorine gas is bubbled through at a slow rate for one half hour togive a solution containing a small amount of suspended startingmaterial. The reaction mixture is stirred for 18 hours at roomtemperature and then the reaction mixture is poured onto ice water withstirring to precipitate5,7-dichloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 121° C.

Analysis: Calculated for C₁₄ H₈ Cl₂ FNO₂ : 53.87%C; 2.59%H; 4.49%N.Found: 53.54%C; 2.59%H; 4.51%N.

b. 10 g of 5,7-dichloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazoleis combined with 100 g pyridine hydrochloride and heated at 200° C. for0.5 hours. The hot melt is quickly poured into stirred ice water and aresultant precipitate is filtered and dried for 48 hours in vacuo (64°C.). The solid is recrystallized from toluene affording5,7-dichloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp194°-196° C.

Analysis: Calculated for C₁₃ H₆ Cl₂ FNO₂ : 52.44%C; 2.01%H; 4.70%N;23.53%Cl. Found: 52.07%C; 2.08%H; 4.96%N; 23.92%Cl.

c. 1.4 g NaH is suspended in 50 ml DMF with stirring. A solution of 7.2g of 5,7-dichloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole in 50ml DMF is added dropwise. The solution is heated to 45° C. for one hour.Ethyl bromoacetate (4.0 g) in 20 ml DMF is added dropwise and thereaction is stirred at 40° C. for two hours. The solution is poured into1 l of water, stirred and extracted with ethyl acetate. The organicextracts are washed with saturated NaCl solution and the solvent removedin vacuo affordingethyl{[5,7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6yl]oxy}acetate,mp 105°-106° C.

Analysis: Calculated for C₁₇ H₁₂ Cl₂ FNO₂ : 53.26%C; 3.13%H; 3.65%N;18.39%Cl. Found: 52.91%C; 3.00%H; 3.41%N; 18.09%Cl.

d. 14.0 g ofethyl{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetateis heated in 75% ethanol/H₂ O (700 ml) with stirring until a solutionresults. 20 ml of a 50% solution of NaOH is added and a precipitateforms. With additional heating and stirring the precipitate goes intosolution and is allowed to stir for 2.5 hours. The ethanol is thenevaporated in vacuo and the residue is made acidic with 10% HCl. Theprecipitated solid is filtered and dried in vacuo to afford{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}aceticacid, mp 160°-170° C.

Analysis: Calculated for C₁₅ H₈ Cl₂ FNO₄ : 50.59%C; 2.26%H; 3.93%N.Found: 50.53%C; 2.32%H; 3.88%N.

EXAMPLE 43

a. To a suspension of NaH (1.0 g) of a 50% dispersion in mineral oil 50ml DMF is added a solution of 5.0 g of7-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole of Example 36cin 50 ml DMF. The solution is stirred one hour at room temperature, thencooled to 5° C. and 3.5 g of N,N-dimethylthiocarbamoyl chloride is addedall at once. The reaction is brought gradually to 60° C. and stirred for2.5 hours. The solution is then poured into water and extracted withmethylene chloride until the extracts are colorless. The combinedorganic extracts are washed with 10% K₂ CO₃, then with saturated NaCl.The solvent is removed in vacuo yielding7-chloro-6-(O-N,N-dimethylthiocarbamyl)-3-(2-fluorophenyl)-1,2-benzisoxazole,mp 153°-154° C.

Analysis: Calculated for C₁₆ H₁₂ ClFN₂ O₂ S: 54.8%C; 3.4%H; 7.9%N;9.1%S. Found: 54.4%C; 3.4%H; 7.9%N; 9.1%S.

b. 4.5 g of7-chloro-6-(O-N,N-dimethylthiocarbamyl)-3-(2-fluorophenyl)-1,2-benzisoxazoleis heated under nitrogen at 205° C. for 45 minutes. A resultant cooledsolid is recrystallized from ethyl acetate affording colorless prisms of7-chloro-6-(S-N,N-dimethylthiocarbamyl)-3-(2-fluorophenyl)-1,2-benzisoxazole,mp 140°-142° C.

Analysis: Calculated for C₁₆ H₁₂ ClFN₂ O₂ S: 54.77%C; 3.44%H; 7.98%N;9.14%S. Found: 54.87%C; 3.56%H; 7.86%N; 9.28%S.

c. 2.0 g of7-chloro-6-(S-N,N-dimethylthiocarbamyl)-3-(2-fluorophenyl)-1,2-benzisoxazoleis dissolved in methanol and 25 ml of 15% aqueous NaOH is added. Thesolution is refluxed for three hours. The reaction mixture is pouredinto a large quantity of water, acidified with HCl to precipitate7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-benzisoxazole, mp 125°-129°C.

Analysis: Calculated for C₁₃ H₇ ClFNOS: 55.81%C; 2.50%H; 5.01%N;11.46%S. Found: 55.94%C; 2.58%H; 5.09%N; 11.52%S.

d. 3.2 g of 7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-benzisoxazole,3.1 g K₂ CO₃ and 3.67 g of ethyl bromoacetate are added to 60 ml DMF andwarmed for two hours at 50° C. with stirring. The solution is pouredinto 700 ml H₂ O and extracted with ethyl acetate. The combined organicextracts are dried over K₂ CO₃, and the solvent is removed in vacuo toaffordethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]thio}acetate.

Analysis: Calculated for C₁₇ H₁₃ ClFNO₃ S: 55.89%C; 3.56%H; 3.83%N;8.76%S. Found: 55.92%C; 3.70%H; 3.80%N; 8.91%S.

e. 1.7 g ofethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]thio}acetateis dissolved in 50 ml of ethanol with stirring and warming. A 50%solution of NaOH is added (3 ml) with 25 ml water and a precipitate of asolid is obtained. After one hour, the ethanol is removed and theresidue is made acidic with HCl. The precipitate is filtered and driedaffording{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]thio}aceticacid, mp 165° C.

Analysis: Calculated for C₁₅ H₉ ClFNO₃ S: 53.41%C; 2.67%H; 4.15%N;9.49%S. Found 53.39%C; 2.68%H; 4.19%N; 9.44%S.

EXAMPLE 44

a. To a solution of o-fluorobenzoyl chloride (47.6 g) in 100 mldichloromethane is added AlCl₃ (40.0 g) portionwise, in about thirtyminutes. To this resultant dark solution is added dropwise a solution of1-chloro-3,5-dimethoxybenzene (52.0 g) in 120 ml dichloromethane, infifteen minutes. After stirring at ambient temperature for four hours,the mixture is poured into one liter iced-dilute HCl solution and thenstirred for 30 minutes. The organic layer is collected, evaporated to anoil, which is dissolved into ether, washed with water, dilute NaOHsolution, water, then dried (saturated NaCl, anhydrous MgSO₄). Afterfiltering, the solvent is evaporated to a solid, which is purified bysilica gel, eluted with dichloromethane to yield2-chloro-4,6-dimethoxy-2'-fluorobenzophenone, mp 88°-92° C.

Analysis: Calculated for C₁₅ H₁₂ ClFO₃ : 61.13%C; 4.11%H; 12.03%Cl;6.45%F. Found: 60.95%C; 4.06%H; 11.85%Cl; 6.38%F.

b. To a solution of 2-chloro-4,6-dimethoxy-2'-fluorobenzophenone (33 g)in 150 ml dichloroethane is added, portionwise in fifteen minutes, AlCl₃(15 g). After stirring at reflux (90° C.) for three hours, the mixtureis cooled, poured into one liter ice-dilute HCl solution, stirred for 30minutes then extracted into ether. The ether/dichloroethane solution iswashed with water, then dried (saturated NaCl, anhydrous MgSO₄) andfiltered.

After filtering, the solvents are evaporated to yield2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone, mp 85°-90° C.

Analysis: Calculated for C₁₄ H₁₀ ClFO₃ : 59.90%C; 3.59%H; 6.77%F. Found:59.78%C; 3.53%H; 7.00%F.

c. To 125 ml pyridine is added2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone (28.5 g) andhydroxylamine hydrochloride (14 g). After stirring at reflux (120° C.)for three hours, the mixture is cooled, the pyridine evaporated to ayellow semi-solid. The solid is dissolved in ether, washed with water,then dried (saturated NaCl, anhydrous MgSO₄). After filtering, thesolvent is evaporated to an oil, which solidifies toZ-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone oxime, mp 130°-140°C., upon trituration with petroluem ether.

Analysis: Calculated for C₁₄ H₁₁ ClFNO₃ : 56.86%C; 3.75%H; 4.74%N.Found: 56.74%C; 3.70%H; 4.74%N.

d. The Z-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone oxime may bereacted with acetic anhydride as described in Example 30c to formE-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone O-acetyl oxime.

e. To a suspension of NaH (2.4 g) in 20 ml DMF, is added a solution ofE-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone O-acetyl oxime (15g) in 50 ml DMF. After stirring at ambient temperature for two hours,the mixture is poured into one l ice-water, stirred for 30 minutes and aprecipitate is collected. The precipitate is washed with water thendried to yield 4-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole,mp 113°-115° C.

Analysis: Calculated for C₁₄ H₁₉ ClFNO₂ : 60.55%C; 3.27%H; 5.05%N.Found: 60.52%C; 3.33%H; 4.96%N.

f. Using 4-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole withthe procedures described in the foregoing examples, such as Example 20dand e, {4-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid, mp 172°-174° C. is obtained.

EXAMPLE 45

a. To a mixture of 3.9 g of AlCl₃ and 4.67 g of 2,3-dichloroanisole in70 ml of 1,2-dichloroethane at -10° C., 5 g of o-methoxybenzoyl chlorideis added dropwise. The mixture is stirred for 2.5 hours and is graduallywarmed to 5° C. The reaction mixture is poured into concentrated HCl andice. The mixture is stirred one half hour to decompose the complex. Theaqueous layer is extracted with additional organic solvent. The combinedorganic layers are washed until neutral, dried over Na₂ SO₄ andevaporated to give an oil which solidifies on trituration with hexane.The crude product is recrystallized from 95% ethanol giving2,3-dichloro-2',4-dimethoxybenzophenone, mp 94°-96° C.

Analysis: Calculated for C₁₅ H₁₂ Cl₂ O₃ : 58.00%C; 3.89%H; Found:57.84%C; 3.81%H;

b. A solid mixture of 13 g of 2,3-dichloro-2',4-dimethoxybenzophenoneand 52 g of pyridine HCl is heated at 200° C. for one hour. The hotmixture is then poured into vigorously stirred ice water. The product isextracted with ethyl acetate. The extract is dried over Na₂ SO₄ andevaporated to give 2,3-dichloro-2',4-dihydroxybenzophenone, mp 197°-201°C.

Analysis: Calculated for C₁₃ H₃ Cl₂ O₃ : 55.15%C; 2.80%H. Found:55.26%C; 2.86%H.

c. To a suspension of 2.87 g of NaH in 150 ml DMF, 30.76 g of2,3-dichloro-2',4-dihydroxybenzophenone in 100 ml of DMF is addedfollowed by the addition of 18.37 g of ethyl bromoacetate. The mixtureis stirred approximately one and one half hours, poured into ice andacid and extracted with CHCl₃. The CHCl₃ extract is dried over Na₂ SO₄and evaporated to give ethyl 2,3-dichloro-4-(2-hydroxybenzoyl)phenoxyacetate, mp 109°-110° C.

Analysis: Calculated for C₁₇ H₁₄ Cl₂ O₅ : 55.30%C; 3.82%H. Found:55.15%C; 3.81%H.

d. Employing ethyl 2,3-dichloro-4-(2-hydroxybenzoyl)phenoxy acetate andthe procedures of the foregoing examples, the corresponding oxime may beformed and cyclized and the ester hydrolyzed to yield[7-chloro-3-2-hydroxyphenyl)-1,2-benzisoxazol-6-yl]oxy acetic acid.

EXAMPLE 46

a. To a stirring solution of phenacetyl chloride (25 g) in 150 ml carbondisulfide, is added AlCl₃ (22 g) portionwise over a period of thirtyminutes, followed by a solution of 2,3-dichloroanisole (28 g) in 50 mlcarbon disulfide.

After stirring at reflux (50° C.) for three hours, the mixture iscooled, then AlCl₃ (22 g) is added and the mixture is stirred at refluxfor two hours. The mixture is cooled, poured into a solution of cold 15%HCl, stirred for 30 minutes then extracted with ethyl acetate/ethylether. The organic extract is washed with water then dried (saturatedNaCl, anhydrous MgSO₄).

After filtering, the solvents are evaporated to give2,3-dichloro-4-phenacetylphenol, mp 173°-180° C.

Analysis: Calculated for C₁₄ H₁₀ Cl₂ O₂ : 59.81%C; 3.59%H. Found:60.15%C; 3.65%H.

b. 2,3-dichloro-4-phenacetylphenol is reacted with hydoxylaminehydrochloride in pyridine as generally described in the foregoingexamples to yield 2,3-dichloro-4-phenacetylphenol oxime.

c. To a suspension of NaH (2.54 g) in 10 ml of dry DMF is added asolution of 2,3-dichloro-4-phenacetylphenol oxime (6.3 g) in 25 ml dryDMF.

After stirring at 80° C. for two hours, the mixture is cooled, then asolution of ethyl bromoacetate (4.2 g) in 10 ml dry DMF is added andstirred at ambient temperature for 30 minutes and then at 60° C. for 30minutes.

After cooling, the mixture is poured into 500 ml of water, stirred for30 minutes, then extracted with ethylacetate. The organic layer iswashed with water then dried (saturated NaCl, anhydrous MgSO₄). Afterfiltering, the solvent is evaporated to an oil from which ethyl{[3-benzyl-7-chloro-1,2-benzisoxazol-6-yl]oxy}acetate was obtained, mp120°-122° C.

Analysis: Calculated for C₁₈ H₁₆ ClNO₄ : 62.52%C; 4.66%H; 4.05%N. Found:62.35%C; 4.74%H; 3.83%N.

d. To 650 ml absolute ethanol is addedethyl{(3-benzyl-7-chloro-1,2-benzisoxazol-6-yl)oxy}acetate (25.0 g),followed by 50% NaOH solution (30 ml). After stirring at reflux (80° C.)for one hour, 500 ml of water is added, the pH adjusted to 1 withconcentrated HCl, then further diluted with 1 liter water. The resultantprecipitate is collected, washed with water, then dissolved indichloromethane. The dichloromethane solution is washed with water, thendried (saturated NaCl, anhydrous MgSO₄).

After filtering, the solvent is evaporated to{(3-benzyl-7-chloro-1,2-benzisoxazol-6-yl)oxy}acetic acid, mp 147°-153°C.

Analysis: Calculated for C₁₆ H₁₂ ClNO₄ : 60.48%C; 3.81%H; 4.41%N;11.16%Cl. Found: 60.36%C; 3.96%H; 4.33%N; 10.91%Cl.

EXAMPLE 47

a. The Friedel-Crafts procedure of Example 46 is repeated with2,3-dichloroanisole, 1-naphthyl chloride and AlCl₃ to yield(2,3-dichloro-4-hydroxyphenyl)(1-naphthyl)methanone.

b. To a solution of 22.48 g of(2,3-dichloro-4-hydroxyphenyl)(1-naphthyl)methanone in 150 ml ofpyridine, 9.87 g of hydroxylamine-hydrochloride are added. The mixtureis refluxed for about 64 hours. Additional hydroxylamine-HCl (9.87 g) isadded and reaction mixture refluxed for 18 hours. The pyridine isevaporated in vacuo and the residue is partitioned between 5% HCl andethyl acetate. The ethyl acetate extract is washed with water, driedover Na₂ SO₄ and evaporated to give a semi-solid product. This productis dissolved in approximately 100 ml of ethyl acetate and passed througha column of charcoal. The filtrate is evaporated to give a solid whichupon trituration with hexane-etheryielded(2,3-dichloro-4-hydroxyphenyl)(1-naphthyl)methanone oxime, mp145°-160° C.

Analysis: Calculated for C₁₇ H₁₁ Cl₂ NO₂ : 61.46%C; 3.34%H; 4.22%N.Found: 61.53%C; 3.45%H; 4.14%N.

c. To a solution of 3 g of(2,3-dichloro-4-hydroxyphenyl)(1-naphthyl)methanone oxime in 25 ml ofDMF, 0.54 g of NaH is added under N₂. The mixture is heated to aninternal temperature of 100° C. for one hour and 20 minutes. Thereaction mixture is cooled to room temperature and 1.65 g of ethylbromoacetate is added dropwise. The mixture is stirred for 18 hours,water is added and the product is extracted with ethyl acetate. Theethyl acetate extract is washed with water, dried over Na₂ SO₄ andevaporated to giveethyl{[7-chloro-3-(1-napthyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp75°-85° C.

Analysis: Calculated for C₂₁ H₁₆ ClNO₄ : 66.06%C; 4.22%H; 3.67%N. Found:65.81%C; 4.24%H; 3.53%N.

d. A suspension of 1.85 g ofethyl-{[7-chloro-3-(1-naphthyl)-1,2-benzisoxazol-6-yl]oxy}acetate, 100ml of ethanol and 2 ml of 50% NaOH is refluxed for one hour. To the hotmixture, 100 ml of water is added followed by enough concentrated HCl tomake the mixture acidic. The reaction mixture is stirred and aprecipitate forms on cooling. Ethanol is evaporated in vacuo and{[7-chloro-3-(1-naphthyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid isfiltered off and dried in vacuum, mp 172°-174° C.

Analysis: Calculated for C₁₉ H₁₂ ClNO₄ : 64.50%C; 3.42%H; 3.96%N. Found:64.51%C; 3.38%H; 3.97%N.

EXAMPLE 48

a. The Friedel-Crafts reaction described in the foregoing examples isrepeated with 2,3-dichloroanisole, 3--fluorobenzoyl chloride and AlCl₃to yield 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone.

b. To a solution of 5 g of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenonein 50 ml of pyridine, 1.58 g of hydroxylamine hydrochloride is added.The mixture is refluxed for 18 hours. The pyridine is evaporated invacuo and the residue is partitioned between 5% HCl and ethylacetate.The ethylacetate is washed with water, dried over Na₂ SO₄ and evaporatedto give 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone oxime as a mixtureof isomers, mp 178°-185° C.

Analysis: Calculated for C₁₄ H₁₀ Cl₂ FNO₂ : 53.52%C; 3.21%H; 4.46%N.Found: 53.66%C; 3.14%H; 4.39%N.

c. To a solution of 3 g of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenoneoxime in 20 ml of DMF, 0.25 g of NaH is added in an atmosphere of N₂.The mixture is stirred for 18 hours. The mixture is heated to 100° C.for one hour. The reaction mixture is poured into ice water to yield7-chloro-3-(3-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 149°-150° C.

Analysis: Calculated for C₁₄ H₉ ClFNO₂ : 60.55%C; 3.26%H; 5.05%N. Found:60.54%C; 3.00%H; 4.91%N.

d. A solid mixture of 14.47 g of7-chloro-3-(3-fluorophenyl)-6-methoxy-1,2-benzisoxazole and 58 g ofpyridine hydrochloride is heated at 190°-200° C. for one hour. The hotmixture is poured into vigorously stirred ice water and7-chloro-6-hydroxy-3-(3-fluorophenyl)-1,2-benzisoxazole is collected byfiltration and washed well with H₂ O, mp 215°-217° C.

Analysis: Calculated for C₁₃ H₇ ClFNO₂ : 59.22%C; 2.68%H; 5.31%N. Found:59.15%C; 2.66%H; 5.16%N.

e. A solution of 10.2 g of7-chloro-6-hydroxy-3-(3-fluorophenyl)-1,2-benzisoxazole is added to amixture of 1.3 g of NaH in 25 ml of DMF. A solution of 6.68 g of ethylbromoacetate in 25 ml of DMF is added and the mixture is stirred for twoand one half hours. 10 ml of 50% NaOH, 175 ml of H₂ O and 30 ml of DMFare added to the reaction mixture which is then heated at 80°-85° C. forone hour. The mixture is made acidic with concentrated HCl, water isadded and {[7-chloro-3-(3-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid is collected by filtration, mp 205°-209° C.

Analysis: Calculated for C₁₅ H₉ ClFNO₄ : 56.00%C; 2.83%H; 4.36%N. Found:55.96%C; 2.81%H; 4.21%N.

EXAMPLE 49

a. To a solution of 1.0 g of4-chloro-3-(o-fluorophenyl)-6-methoxy-1,2-benzisoxazole, of Example 44e, in 50 ml glacial acetic acid is added chlorine gas (the solution ispurged for five minutes). After stirring at ambient temperature for onehour, the mixture is poured into 500 ml water, stirred for fifteenminutes and a resultant precipitate is extracted into ether/ethylacetate. The organic layer is washed with water, then dried (saturatedNaCl, anhydrous MgSO₄) and after filtering the solvents are evaporatedto yield 3-(o-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole,mp 120°-140° C.

Analysis: Calculated for C₁₄ H₇ Cl₃ FNO₂ : 48.51%C; 2.04%H. Found:48.15%C; 2.27%H.

b. The procedures of Examples 20d and e may be employed with3-(o-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole to yield{[4,5,7-trichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid.

EXAMPLE 50

10 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole ofExample 36 c is dissolved in 70 ml DMF and 7.86 g K₂ CO₃ is added withstirring. 3.6 ml of chloroacetonitrile is added and the mixture isstirred 0.5 hours at room temperature, then raised to 55° C. for 2hours. Stirring is continued 15 hours at room temperature and 1.5 ml ofchloroacetonitrile is added and the reaction stirred 6 hours at 50° C.It is poured into a large volume of ice/H₂ O and{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetonitrilewhich is precipitated is collected by filtration, mp 147° C.

Analysis: Calculated for C₁₅ H₈ ClFN₂ O₂ : 59.51%C; 2.66%H; 9.25%N.Found: 59.38%C; 2.67%H; 9.36%N.

EXAMPLE 51

15 g 7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole in 75 mlDMF is added to a suspension of 3.0 g NaH in 75 ml DMF. After one hourat room temperature, 16.7 ml of ethyl-2-bromoisobutyrate is added. After72 hours at 50° C. the reaction mixture is poured into ice/HCl andextracted with CH₂ Cl₂ and the organic phase is washed with 5% K₂ CO₃,followed by washing with saturated NaCl. It is dried over MgSO₄,filtered and is evaporated to a brown oil. The oil is distilled atreduced pressure to remove unreacted ethyl-2-bromoisobutyrate and theresidue is triturated with ether/petroleum ether, filtered and themother liquor is evaporated to an oil which is distilled (200° C., 0.1mm) affordingethyl-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}-2-methylpropionate.

Analysis: Calculated for C₁₉ H₁₇ ClFNO₄ : 60.6%C; 4.53%H; 3.70%N. Found:60.0%C; 4.72%H; 3.60%N.

EXAMPLE 52

a. To a mixture of 46 g of 4-chloro-2-fluorobenzoyl chloride and 38.9 gof 2,3-dichloroanisole in 150 ml of 1,2-dichloroethane, 32 g of AlCl₃ isadded gradually. The mixture is warmed to 40° C. with a vigorousevolution of gas. The mixture is poured into concentrated HCl and ice.The organic layer is separated and the aqueous layer is extracted withadditional organic solvent. The combined organic extracts are washedwith water, dried over Na₂ SO₄ and evaporated. The crude product istriturated with hexane to give2,3-dichloro-4-methoxy-4'-chloro-2'-fluorobenzophenone. An analyticalsample is recrystallized from EtOH, mp 115°-116° C.

Analysis: Calculated for C₁₄ H₈ Cl₃ FO₂ : 50.41%C; 2.42%H; 5.80%F.Found: 50.11%C; 2.36%H; 6.17%F.

b. In a manner similar to that of Example 21 b,2,3-dichloro-4-methoxy-4'-chloro-2'-fluorobenzophenone is converted into2,3-dichloro-4-methoxy-4'-chloro-2'-fluorobenzophenone oxime.

c. To a mixture of 2.24 g of NaH in 100 ml DMF, 21.75 g of2,3-dichloro-4-methoxy-4'-chloro-2'-fluorobenzophenone oxime in 100 mlof DMF is added dropwise. After addition the mixture is stirred one hourand the reaction mixture poured into ice water. A product whichprecipitates is filtered and dried giving a mixture of isomers which ischromatographed on silica gel with 50% hexane and 50% toluene as eluantto yield7-chloro-3-(4-chloro-2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp193°-194° C.

Analysis: Calculated for C₁₄ H₈ Cl₂ FNO₂ : 53.87%C; 2.58%H; 4.49%N.Found: 54.01% C; 2.56%H; 4.44%N.

d. A solid mixture of 5.4 g of7-chloro-3-(4-chloro-2-fluorophenyl)-6-methoxy-1,2-benzisoxazole and22.4 g of pyridine HCl is heated at 200° C. for two hours. The reactionmixture is then poured into vigorously stirring ice water and ademethylated product is obtained.

To a solution of 3.9 g of the demethylated product in 40 ml of DMF, 1.9g of K₂ CO₃ and 2.3 g of ethyl bromo acetate are added. The reaction iswarmed to 60° C. for two hours and permitted to stand 18 hours. To thereaction mixture 100 ml of water and 10 ml of 50% NaOH are added. Themixture is heated at 90° C. for 90 minutes and the reaction mixture ispoured into water, acidified and extracted with ethyl acetate, dried andevaporated to yield{[7-chloro-3-(4-chloro-2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid, mp 226°-227° C.

Analysis: Calculated for C₁₅ H₈ Cl₂ FNO₄ : 50.59%C; 2.26%H; 3.93%N.Found: 50.39%C; 2.24%H; 4.06%N.

EXAMPLE 53

To a suspension of 0.9 g lithium aluminum hydride (98%) in 100 mlanhydrous ether is added a solution of 10 gethyl-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetateof Example 1 d in 200 ml ether containing sufficient tetrahydrofuran toeffect solution. The reaction mixture is stirred for two hours at roomtemperature and one hour at reflux. To the reaction mixture is added 0.9ml H₂ O, 0.9 ml 15% NaOH and 2.7 ml H₂ O. The stirred suspension isfiltered and the filtrate is concentrated to afford2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}ethanol, mp112° C.

Analysis: Calculated for C₁₅ H₁₁ ClFNO₃ : 58.63%C; 3.58%H; 4.56%N.Found: 58.48%C; 3.62%H; 4.49%N.

EXAMPLE 54

4.5 g ofethyl-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}-2-methylpropionate,of Example 51, is dissolved in 35 ml methanol and 30 ml of a 15% NaOHsolution is added thereto. The suspension is heated at reflux for 4hours and then poured into ice-water, and acidified, producing an oilyprecipitate. This precipitate is extracted with ether and the etherextracts are washed with 10% NaHCO₃. The basic extracts are acidifiedwith concentrated HCl and chilling thereof affords2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}-2-methylpropionic acid, mp 108° C.

Analysis: Calculated for C₁₇ H₁₃ ClFNO₄ : 58.45%C; 3.72%H; 4.01%N.Found: 58.39%C; 3.75%H; 3.96%N.

EXAMPLE 55

3.35 g NaN₃ and 2.25 g of AlCl₃ are stirred in 50 ml THF at reflux for0.5 hour. A solution of 5 g{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetonitrile,of Example 50, in 50 ml THF is added and the reaction mixture is stirredat reflux for about 120 hours. To the reaction mixture is added waterand the solvent is removed. The residue is treated with dilute HCl andextracted with CHCl₃. Upon attempted extraction of the chloroformsolution with 15% NaOH a precipitate forms which is filtered, dissolvedin hot water and acidified to afford 7-chloro-3-(2-fluorophenyl)-6-{[5-tetrazolylmethyl]oxy}-1,2-benzisoxazole, mp 198°-200° C.

Analysis: Calculated for C₁₅ H₉ ClFN₅ O₂ : 52.17%C; 2.60%H; 20.28%N.Found: 52.02%C; 2.69%H; 20.37%N.

EXAMPLE 56

To a solution of 10.0 g of{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid in70 ml of ice-cold sulfuric acid, 2.5 ml of 16N nitric acid is added. Thereaction mixture is stirred for 2 hr in the cold and then allowed towarm to room temperature over 1 hr. The reaction mixture is then pouredonto ice and the solid is collected. The filter cake is washed withwater until the washes are no longer acidic and then recrystallized fromacetic acid to afford{[7-Chloro-3-(2-fluoro-5-nitrophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid, mp 238°-240° C.

Analysis: Calculated for C₁₅ H₈ ClFN₂ O₆ : 49.13%C; 2.05%H; 7.60%N.Found: 48.72%C; 2.00%H; 7.57%N.

EXAMPLE 57

To a solution of 10.9 g of{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid in70 ml of ice-cold sulfuric acid, 2.2 ml of 16N nitric acid is added. Thereaction mixture is stirred in the cold for 2 hr, allowed to warm toroom temperature over 1 hr and poured into ice-water. The precipitate iscollected to afford{[7-chloro-3-(2-fluoro-5-nitrophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid. The fluoro-compound is treated with excess sodium methoxide inrefluxing methanol for a total of 48 hr. The reaction mixture isacidified and the product is collected by filtration. Recrystallizationfrom acetonitrile affords{[7-Chloro-3-(2-methoxy-5-nitrophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid, mp 260°-262° C. (dec.)

Analysis: Calculated for C₁₆ H₁₁ ClN₂ O₇ : 50.74%C; 2.93%H; 7.40%N.Found: 50.27%C; 2.87%H; 7.43%N.

EXAMPLE 58

A solution of 5.0 g of7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole in 30 mldimethylformamide is added to a suspension of 1 g (50% suspension inoil) sodium hydride in 30 ml of dimethylformamide with stirring.Bromoacetaldehyde diethylacetal (6.2 ml) is added and the reactionmixture is heated at 80° C. for 24 hrs. The resulting dark solution ispoured onto ice/water and extracted with four-100 ml portions of ether.The combined ether extracts are washed with dilute sodium hydroxidesolution, saturated sodium chloride solution and dried over anhydrousmagnesium sulfate. Removal of the solvent followed by recrystallizationfrom ether/petroleum ether affords{[7-chloro-3(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetaldehydediethyl acetal as white needles, mp 59° C.

Analysis: Calculated for C₁₉ H₁₉ ClFNO₄ : 60.08%C; 5.04%H; 3.68%N.Found: 59.92%C; 4.91%H; 3.59%N.

EXAMPLE 59

To a solution of 1.00 g of hydroxylamine hydrochloride in 50 ml of 1:1ethanol/water and 4 ml of 50% sodium hydroxide is added 5.0 g of ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate in smallportions, adding methanol as necessary to achieve solution. Afterstirring for 18 hr (a solid is formed), hydrochloric acid is added to pH6. The solvent is evaporated, water is added to the residue and themixture extracted with ether. The extracts are dried over anhydrousmagnesium sulfate, filtered and evaporated. Recrystallization fromtoluene-acetonitrile affords{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetohydroxamicacid as a white solid mp 151° C.

Analysis: Calculated for C₁₅ H₁₀ ClFN₂ O₄ : 53.50%C; 2.99%H; 8.32%N.Found: 53.23%C; 2.94%H; 8.18%N.

EXAMPLE 60

To 12.5 g of3-(2-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole is added80.0 g of pyridine hydrochloride. The mixture is immersed in an oil bathat 200° C. for thirty minutes with stirring. The melt is poured into oneliter of iced-hydrochloric acid solution, stirred for thirty minutes,and the resultant precipitate collected and dried to yield3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, mp 110°C. (dec). To 50 ml of dry dimethylformamide is added 12 g of3-(2-fluorophenyl)-6-hydroxy-4,5,7-trichloro-1,2-benzisoxazole, 4.4 mlof ethyl bromoacetate and 20 g of potassium carbonate. The reaction isstirred at 70° C. for 2 hrs, filtered and solvent evaporated to affordan oil, which is stirred with 500 ml water for ten minutes and thenextracted with ether/ethyl acetate. The organic extract is washed withwater (2X), saturated sodium chloride solution, dried over anhydrousmagnesium sulfate and filtered. Evaporation of the filtrate followed byrecrystallization from 95% ethanol yields ethyl{[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}acetate,mp 140°-3° C.

Analysis: Calculated for C₁₇ H₁₁ Cl₃ FNO₄ : 48.77%C; 2.65%H; 3.35%N.Found: 48.75%C; 2.55%H; 3.43%N.

EXAMPLE 61

A solution of 4.0 g of{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloridein methylene chloride is added dropwise to a solution of 0.9 g ofmethylamine hydrochloride in 50 ml methylene chloride and 25 ml of 15%sodium hydroxide solution at 0° C. After 18 hr at room temperature thereaction mixture is acidified, filtered, and the filtrate partitioned.The aqueous solution is washed with methylene chloride. The organicsolutions are combined, washed with saturated sodium chloride solutionand dried over magnesium sulfate. Removal of the solution givesN-methyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide,mp 164° C.

Analysis: Calculated for C₁₆ H₁₂ ClFN₂ O₃ : 57.40%C; 3.61%H; 8.37%N.Found: 57.13%C; 3.66%H; 8.12%N.

EXAMPLE 62

To 3.5 g of{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chlorideis added 50 ml of conc ammonium hydroxide at 0° C. After stirring for 2hr the precipitate is filtered and washed with ice-cold acetonitrile.Recrystallization of the filter cake from acetonitrile gives}[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide, mp172° C.

Analysis: Calculated for C₁₅ H₁₀ ClFN₂ O₃ : 56.17%C; 3.14H; 8.74%N.Found: 56.01%C; 3.19%H; 8.57%N.

EXAMPLE 63

A solution of 3.5 g of{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloridein 35 ml dimethylformamide is heated at 100° C. for 4 hr. The reactionmixture is then poured into ice, acidified and extracted with ether(4×200 ml). The organic extracts are washed with saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered andthe filtrate evaporated in vacuo to afford an oil which crystallizes ontrituration with ether/petroleum ether. Chromatography on silica gelaffordsN,N-dimethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamidemp 116° C.

Analysis: Calculated for C₁₇ H₁₄ ClFN₂ O₃ : 58.54%C; 4.04%H; 8.03%N.Found: 58.31%C; 4.00%H; 7.82%N.

EXAMPLE 64

To a suspension of 3.0 g of ethyl{[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}acetatein 50 ml of ethanol, is added 8 ml of 10% sodium hydroxide solution.After stirring at room temperature for ten minutes a solid begins toprecipitate from solution. Stirring is continued for thirty minutes.Water (20 ml) is added and the precipitate dissolves. The reactionmixture is poured into 500 ml of dilute hydrochloric acid, stirred for15 minutes, and the resultant precipitate is collected and dried at 60°C. overnight in a vacuum oven. Recrystallization from toluene yields{[3-(2-fluorophenyl)-4,5,6-trichloro-1,2-benzisoxazol-6-yl]oxy}aceticacid mp 222°-4° C.

Analysis: Calculated for C₁₅ H₇ Cl₃ FNO₄ : 46.12%C; 1.81%H; 3.59%N.Found: 46.38%C; 1.86%H; 3.47%N.

EXAMPLE 65

A solution of 4.0 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in20 ml dimethylformamide is added dropwise with stirring to 0.86 g ofsodium hydride (50% suspension in oil) which is washed with hexane anddispersed in 20 ml dimethylformamide. A precipitate forms. When theaddition is complete, the reaction mixture is stirred for 20 min and2.28 ml of ethyl bromoacetate is added. The reaction mixture is pouredinto ice/water with stirring and the resultant precipitate is filteredand dried. Recrystallization from ether gives ethyl{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 97° C.

Analysis: Calculated for C₁₇ H₁₄ ClNO₄ : 61.63%C; 4.23%H Found: 61.34%C;4.07%H

EXAMPLE 66

A solution of 4.5 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in10 ml of dimethylformamide is added dropwise to 1.0 g of sodium hydride(50% susp. in oil) which is washed with hexane and then suspended in 60ml dimethylformamide. Ethyl-2-bromopropionate (3.67 ml) is added. Thereaction mixture is poured into ice/water with stirring and the solid iscollected. Recrystallization from ether affordsethyl-2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}propionate, mp95° C.

Analysis: Calculated for C₁₈ H₁₆ ClNO₄ : 62.61%C; 4.63%H. Found:62.61%C; 4.60%H.

EXAMPLE 67

A suspension of 4 g of ethyl{[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate in 125 mlof ethanol, 50 ml of water and 4 ml of 50% sodium hydroxide solution isrefluxed for several hours, acidified with dilute hydrochloric acid andextracted with ethyl acetate. The extract is dried, the solvent isremoved and the residue is recrystallized from acetonitrile to give{[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp223°-224° C.

Analysis: Calculated for C₁₅ H₉ BrFNO₄ : 49.20%C; 2.48%H; 3.83%N. Found:49.14%C; 2.49%H; 3.76%N.

EXAMPLE 68

A solution of sodium ethoxide, prepared from 0.50 g of sodium and 15 mlof absolute ethanol is added to a stirred suspension of 6.0 g of{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetonitrile and1.4 g of hydroxylamine hydrochloride in 60 ml of absolute ethanol. Thereaction mixture is refluxed for 30 min, poured into water and theprecipitate is collected and dried. The precipitate is dissolved in warmmethanol and treated with ethereal hydrogen chloride to giveN-hydroxy-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetimidamide,mp 218° C. (dec.).

Analysis: Calculated for C₁₅ H₁₁ ClFN₃ O₃ HCl: 48.41%C; 3.25%H; 11.29%N.Found: 48.31%C; 3.25%H; 11.32%N.

EXAMPLE 69

A solution of 5.3 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in30 ml of dimethylformamide is added dropwise to a suspension of 0.65 gof sodium hydride (50% suspension in oil) in 30 ml of dimethylformamide.After stirring for 20 min, 1.4 ml of ethyl bromoacetate is added. Thereaction mixture is stirred for 1 hr, poured into water and theprecipitate is collected. The precipitate is added to 30 ml of 15%sodium hydroxide solution and 30 ml methanol and heated at reflux for 3hr. The mixture is poured into water, acidified and filtered.Recrystallization from toluene and acetonitrile gives{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-acetic acid, mp 207° C.

Analysis: Calculated for C₁₅ H₁₀ ClNO₄ : 59.21%C; 3.29%H. Found:58.93%C; 3.34%H.

EXAMPLE 70

a. 2-Bromoresorcinol dimethyl ether is condensed with 2-fluorobenzoylchloride to give 5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone whichis reacted with hydroxylamine hydrochloride to affordE-5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone and converted withacetic anhydride to E-5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenoneO-acetyl oxime, all steps being performed by the process of Example 37.E-5-bromo-2'-fluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime iscyclized to 5-bromo-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole anddemethylated to 5-bromo-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole,both steps being performed by the process of Example 35.

b. A mixture of 12 g of5-bromo-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, 10.8 g ofpotassium carbonate and 7.8 g of ethyl bromoacetate in 200 ml of2-butanone is stirred at reflux for 6 hours. The reaction mixture isfiltered and the solvent removed from the filtrate under vacuum.Recrystallization of the residue from ether-chloroform-hexane givesethyl {[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp130°-132° C.

Analysis: Calculated for C₁₇ H₁₃ BrFNO₄ : 51.79%C; 3.33%H; 3.55%N.Found: 51.50%C; 3.10%H; 3.51%N.

EXAMPLE 71

A mixture of 11.6 g of7-bromo-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, 17.5 g of ethylbromoacetate, 13.3 g of potassium carbonate and 100 ml ofdimethylformamide is heated at 65° C. for 5 hr. The reaction mixture ispoured into water and the mixture is extracted with ether. The etherextracts are washed, dried and evaporated to afford ethyl{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp130°-131° C.

Analysis: Calculated for C₁₇ H₁₃ BrFNO₄ : 51.79%C; 3.33%H; 3.55%N.Found: 51.95%C; 3.28%H; 3.54%N.

EXAMPLE 72

To a mixture of 4.5 g of 3-(4-chlorophenyl)-6-thiol-1,2-benzisoxazole, 5g of potassium carbonate in 50 ml of dimethylformamide is added, withstirring, 2.00 ml of ethyl 2-bromopropionate. The mixture is heated to95° C. for 3 hr. The reaction mixture is poured with stirring ontoice/dil hydrochloric acid. The aqueous suspension is extracted withethyl ether (3×200 ml) and the extracts are dried over anhydrousmagnesium sulfate. Evaporation of the solvent affords an oil which ontrituration with isopropyl ether gives a solid. Recrystallization fromisopropyl ether affords ethyl2-{[3-(4-chlorophenyl-1,2-benzisoxazol-6-yl]thio}propionate, mp 74° C.

Analysis: Calculated for C₁₈ H₁₆ ClNO₃ S: 59.83%C; 4.43%H; 8.86%S.Found: 59.84%C; 4.54%H; 8.62%S.

EXAMPLE 73

A solution of 9.0 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in25 ml of dimethylformamide is added with stirring to a suspension of1.93 g of sodium hydride (50% suspension in oil) in 25 mldimethylformamide. To the mixture is added 5.5 ml of ethyl2-bromo-2-methylpropionate. The reaction mixture is stirred 24 hr at 80°C., poured onto ice/water and extracted with ether. The ether extractsare combined and washed with dil sodium hydroxide solution and driedover anhydrous magnesium sulfate. The solvent is removed in vacuo togive a yellow oil which crystallizes on standing. Recrystallization fromether affords ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-2-methylpropionate, mp70° C.

Analysis: Calculated for C₁₉ H₁₈ ClNO₄ : 63.51%C; 5.01%H. Found:63.29%C; 5.07%H.

EXAMPLE 74

A mixture of 14.2 g of7-chloro-3-(4-ethoxy-2-fluorophenyl)-6-methoxy-1,2-benzisoxazole andpyridine hydrochloride is heated at 180° C. for 2 hr. The reaction isworked up with 2-butanone and 5% hydrochloric acid and the productcrystallized from toluene to give7-chloro-3-(4-ethoxy-2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp170°-172° C. The hydroxy compound is alkylated with 0.045 mole of ethylbromoacetate and 0.043 mole of potassium carbonate in 75 mldimethylformamide at 65° C. for 1 hr. Workup with water gives ethyl[7-chloro-3-(2-fluoro-4-ethoxyphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate,mp 118°-119° C., after recrystallization from acetonitrile.

Analysis: Calculated for C₁₉ H₁₇ ClFNO₅ : 57.95%C; 4.35%H; 3.56%N.Found: 58.06%C; 4.28%H; 3.52%N.

EXAMPLE 75

A mixture of 3.2 g of 3-(4-chlorophenyl)-6-mercapto-1,2-benzisoxazole,2.52 g of potassium carbonate, 2.39 g ofethyl-2-bromo-2-methylpropionate and 75 ml dimethylformamide is heatedat 60° C. for 8 hr. The reaction mixture is poured onto ice/dilhydrochloric acid and extracted with ether. The combined ether extractsare washed with dil sodium hydroxide solution, saturated sodium chloridesolution and the solvent is removed in vacuo to afford a yellow oil. Theoil is distilled in a Kugelrohr oven at 175° C. and 1.0 mm Hg to give anoil which crystallizes on standing. The solid is recrystallized fromisopropyl ether using a brine-chilled Buchner funnel to afford ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate.

Analysis: Calculated for C₁₉ H₁₈ ClNO₃ S: 60.8%C; 4.8%H. Found: 60.7%C;4.8%H.

EXAMPLE 76

A solution of 9.3 g of ethyl{[7-chloro-3-(2-fluoro-4-ethoxyphenyl)-1,2-benzisoxazol-6-yl]oxy}acetatein 120 ml of methylene chloride is treated with 11.3 g of borontribromide. The mixture is refluxed for 2 hr and then an additional 3.8g of boron tribromide is added. Another 3.8g of boron tribromide isadded after 3 hr of reflux and then the reaction mixture is quenchedwith water after a total of 4 hr of reflux. The crude product which isisolated by diethyl ether extraction is hydrolyzed by heating underreflux in 100 ml ethanol and 150 ml 5% sodium hydroxide for 30 min. Theprecipitate is collected and the acid is isolated by distributionbetween 2-butanone and 5% hydrochloric acid and recrystallized fromacetic acid. Additional product is obtained from the mother liquors bychromatography over silica gel, eluting successively with methylenechloride, 5% acetic acid/methylene chloride, 10% acetic acid/methylenechloride and 20% acetic acid/methylene chloride. The combined productsare recrystallized twice from toluene/acetic acid to give{[7-chloro-3-(2-fluoro-4-hydroxyphenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid, mp 216°-218° C.

Analysis: Calculated for C₁₅ H₉ ClFNO₅ : 53.35%C; 2.69%H; 4.15%N. Found:53.68%C; 2.80%H; 4.15%N.

EXAMPLE 77

To 3.3 g of ethyl2-{[3-(4-chlorophenyl-1,2-benzisoxazol-6-yl]oxy}butyrate and 25 ml ofmethanol is added 20 ml of 15% sodium hydroxide solution. The suspensionis stirred at reflux for 45 min. The methanol is then removed byevaporation and the basic solution is poured into dilute hydrochloricacid/ice. The precipitate is collected and dried. The solid isrecrystallized from toluene to give2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-2-methylpropionicacid, mp 132° C.

Analysis: Calculated for C₁₇ H₁₄ ClNO₄ : 61.63%C; 4.23%H. Found:61.78%C; 4.24%H.

EXAMPLE 78

A mixture of 6.5 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole,7.5 g of potassium carbonate, 5.16 g of ethyl 2-bromobutyrate and 100 ml2-butanone is heated under reflux with stirring for 5 hr. The reactionmixture is poured into ice/dil hydrochloric acid. The oil, whichsolidified on scratching, was collected and dried in vacuo.Recrystallization from isopropyl ether (decolorizing carbon) gives ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyrate, mp 73° C.

Analysis: Calculated for C₁₉ H₁₈ ClNO₄ : 63.51%C; 5.01%H. Found:63.24%C; 5.06%H.

EXAMPLE 79

A solution of 3.6 g ofethyl-2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyrate, 30 mlof 15% sodium hydroxide solution and 30 ml of methanol, is stirred underreflux for 3 hr. The methanol is evaporated and the solution is pouredinto dilute hydrochloric acid/ice affording a flocculant precipitate.The precipitate is collected, dried in vacuo and recrystallized fromtoluene to afford2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyric acid, mp 144°C.

Analysis: Calculated for C₁₇ H₁₄ ClNO₄ : 61.63%C; 4.24%H. Found:61.59%C; 4.27%H.

EXAMPLE 80

A solution of 3.7 g of ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate,30 ml of 15% sodium hydroxide solution and 30 ml of methanol, is stirredunder reflux for 3 hr. The methanol is evaporated and the aqueoussolution poured into ice/dilute hydrochloric acid. The precipitate iscollected, dried and recrystallized from toluene to afford2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionicacid, mp 176°-7° C.

Analysis: Calculated for C₁₇ H₁₄ ClNO₃ S: 58.78%C; 4.03%H. Found:58.81%C; 4.08%H.

EXAMPLE 81

A solution of 6 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole,10.2 g of potassium carbonate, 5.12 g of ethyl 2-bromovalerate and 100ml of methylethyl ketone is stirred under reflux for 3 hr. The reactionmixture is poured into 1 liter of ice/dil hydrochloric acid and theprecipitate is collected and dried. Recrystallization from ether givesethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoate, mp88° C.

Analysis: Calculated for C₂₀ H₂₀ ClNO₄ : 64.34%C; 5.36%H. Found:64.20%C; 5.37%H.

EXAMPLE 82

A solution of 3.5 g of ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoate, 30 ml 15%sodium hydroxide and 30 ml methanol is heated under reflux for 1.5 hr.The reaction mixture is poured into ice/dil hydrochloric acid withstirring. The precipitate is collected, washed with water and dried invacuo. Recrystallization from toluene/acetonitrile affords2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoic acid, mp 170°C.

Analysis: Calculated for C₁₈ H₁₆ ClNO₄ : 62.60%C; 4.63%H. Found:62.42%C; 4.65%H.

EXAMPLE 83

A solution of 8 g of7-chloro-3-(2-fluorophenyl)-6-thiol-1,2-benzisoxazole, 12.0 g ofpotassium carbonate, 7.2 ml of ethyl-2-bromoisobutyrate and 150 ml of2-butanone is heated under reflux for 2 hr. The reaction mixture ispoured into 1 liter of ice and water and extracted with ether (3×300ml). The combined organic extracts are washed with saturated sodiumchloride solution, dried over anhydrous magnesium sulfate and thesolvent is evaporated at reduced pressure to give an oil, whichcrystallized on standing. Recrystallization from hexane containing alittle ether gives ethyl2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate,mp 83.4° C.

Analysis: Calculated for C₁₉ H₁₇ ClFNO₃ S: 57.93%C; 4.35%H. Found:57.65%C; 4.34%H.

EXAMPLE 84

A mixture of 5.0 g of ethyl2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate,30 ml of 15% sodium hydroxide and 30 ml of methanol is heated underreflux for 2 hr. The reaction mixture is poured into ice/conchydrochloric acid. The precipitate is collected, dried andrecrystallized from toluene to afford2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionicacid, mp 149° C.

Analysis: Calculated for C₁₇ H₁₃ ClFNO₃ S: 55.89%C; 3.56%H. Found:55.74%C; 3.53%H.

EXAMPLE 85

A solution of 7.32 g of{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, 135ml of dry tetrahydrofuran and 2.02 g of triethylamine is added dropwiseto a solution of 2.16 g of ethyl chloroformate in ice-coldtetrahydrofuran. The precipitate is filtered off. A solution of 0.80 gof sodium hydroxide in 25 ml of hot methanol is added to a solution of1.4 g of hydroxylamine hydrochloride in 25 ml of hot methanol. Theprecipitate is collected. The solution is added to the tetrahydrofuranfiltrate. The reaction mixture is warmed for 15 min of a steam bath,poured into water and extracted with 2-butanone. Evaporation andrecrystallization from nitromethane gives{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetohydroxamicacid, mp 165°-167° C.

Analysis: Calculated for C₁₅ H₁₀ BrFN₂ O₄.0.2H₂ O: 46.71%C; 2.74%H;7.27%N. Found: 46.65%C; 2.63%H; 6.99%N.

EXAMPLE 86

a. To a mixture of 30 g of 2,5-difluorobenzoyl chloride and 23.5 g of1,3-dimethoxybenzene in 300 ml 1,2-dichloroethane, 23 g of aluminumchloride is added in portions with the internal temperature maintainedat approximately 8°-12° C. The reaction mixture is stirred 0.5 hr andrefluxed one hr. The reaction mixture is poured into concentratedhydrochloric acid and ice. The organic layer is separated, washed, driedover anhydrous sodium sulfate and evaporated. Trituration of the cruderesidue gives 2',5'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 109° C.followed by recrystallization from toluene.

Analysis: Calculated for C₁₄ H₁₀ F₂ O₃ : 63.64%C; 3.81%H. Found:64.01%C; 3.80%H.

b. A mixture of 40 g of 2',5'-difluoro-2-hydroxy-4-methoxybenzophenonehydrochloride and 230 ml of pyridine is refluxed overnight. The pyridineis evaporated in vacuo. The residue is partitioned between 5%hydrochloric acid and ethyl acetate. The ethyl acetate solution is driedover anhydrous sodium sulfate and evaporated. The residue was trituratedwith hexane to give E-2',5'-difluoro-2-hydroxy-4-methoxybenzophenoneoxime. A mixture of 35 g of the oxime and 25.6 g of acetic anhydride isplaced in an oil bath at 60° C. for 45 min. The reaction mixture ispartitioned between ether and sodium bicarbonate solution. The etherextract is dried over anhydrous sodium sulfate and evaporated.Recrystallization of the residue from 95% ethanol gives 30 g ofE-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp110°-111° C.

Analysis: Calculated for C₁₆ H₁₃ F₂ NO₄ : 59.81%C; 4.07%H. Found:59.67%C; 3.84%H.

c. To a mixture of 34 g ofE-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime in 70 mldimethylformamide at 65° C., 18.2 g of potassium carbonate is added. Themixture is stirred for 45 min and poured into water. The precipitate iscollected and dried. Recrystallization from ether gives3-(2,5-difluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 121°-122° C.

Analysis: Calculated for C₁₄ H₉ F₂ NO₂ : 63.64%C; 3.81%H. Found:63.79%C; 3.75%H.

d. 3-(2,5-Difluorophenyl)-6-methoxy-1,2-benzisoxazole may bedemethylated by the procedure described in Example 60 to3-(2,5-difluorophenyl)-6-hydroxy-1,2-benzisoxazole which in turn may becondensed with ethyl bromoacetate according to the method described inExample 60 to ethyl{[3-(2,5-difluorophenyl-1,2-benzisoxazol-6-yl]oxy}acetate and hydrolyzedby the process disclosed in Example 64 to{[3-(2,5-difluorophenyl-1,2-benzisoxazol-6-yl]oxy}acetic acid.

EXAMPLE 87

a. To a mixture of 20 g of 2,6-difluorobenzoyl chloride and 15.5 g of1,3-dimethoxybenzene in 200 ml of 1,2-dichloroethane, 15.28 g ofaluminum chloride is added in portions with the internal temperaturemaintained at 0°-10° C. The mixture is stirred 1 hour and then refluxed45 min. The reaction mixture is poured into concentrated hydrochloricacid and ice. The organic layer is separated, washed, dried overanhydrous sodium sulfate and evaporated. Trituration with hexanefollowed by recrystallization from 95% ethanol gives2',6'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 71°-72° C.

Analysis: Calculated for C₁₄ H₁₀ F₂ O₃ : 63.64%C; 3.81%H. Found:63.79%C; 3.75%H.

b. 2',6'-Difluoro-2-hydroxy-4-methoxybenzophenone may be condensed withhydroxylamine to E-2',6'-difluoro-2-hydroxy-4-methoxybenzophenone oximewhich in turn may be converted toE-2',6'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime andcyclized to 3-(2,6-difluorophenyl)-6-methoxy-1,2-benzisoxazole, allsteps being performed by the procedures described in Example 86.3-(2',6'-Difluorophenyl)-6-methoxy-1,2-benzisoxazole then may bedemethylated to 3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole andcondensed with ethyl bromoacetate to ethyl{[3-(2,6-difluorophenyl-1,2-benzisoxazol-6-yl]oxy}acetate both stepsbeing performed by the methods disclosed in Example 64. Ethyl{[3-(2,6-difluorophenyl-1,2-benzisoxazol-6-yl]oxy}acetate may behydrolyzed to {[3-(2,6-difluorophenyl-1,2-benzisoxazol-6-yl]oxy}aceticacid.

EXAMPLE 88

a. 4'-Chloro-2-hydroxy-4-methoxybenzophenone is prepared by condensingresorcinal dimethyl ether with 4-chlorobenzoyl chloride in the presenceof aluminum chloride according to the procedure of Example 37.

b. A mixture of 382 g of 4'-chloro-2-hydroxy-4-methoxybenzophenone, 230g hydroxylamine hydrochloride and 1.5 liters of pyridine is heated underreflux for 3 hr. The solvent is evaporated and the residue ispartitioned between hydrochloric acid and ethyl acetate. The organicextracts are combined and washed with saturated sodium chloridesolution. The solvent is removed to afford a mixture of E- and Z-oximeisomers which is separated on a Waters Prep IC System 500 using 5% ethylacetate/toluene as the eluting system to affordE-4'-chloro-2-hydroxy-4-methoxybenzophenone oxime, mp 159° C.

Analysis: Calculated for C₁₄ H₁₂ ClNO₃ : 60.64%C; 4.34%H. Found:60.54%C; 4.33%H.

EXAMPLE 89

A solution of E- and Z-4'-chloro-2-hydroxy-4-methoxybenzophenone and 19ml acetic anhydride is heated for 1 hr at 60° C. The reaction mixture ispoured into ice-water and extracted with chloroform. The extracts aredried over anhydrous magnesium sulfate and the solvent is evaporated.Recrystallization from ether hexane affordsE-4'-chloro-2-hydroxy-4-methoxybenzophenone-O-acetyl oxime, mp 167° C.

Analysis: Calculated for C₁₆ H₁₄ ClNO₄ : 60.18%C; 4.38%H. Found:59.97%C; 4.38%H.

EXAMPLE 90

A mixture of 5.32 g ofE-4'-chloro-2-hydroxy-4-methoxybenzophenone-O-acetyl oxime, 3.45 g ofpotassium carbonate and 50 ml of 2-butanone is heated under reflux at80° C. for 2 hr. The reaction mixture is poured into water/ice. Theprecipitate is filtered, dried, and recrystallized from toluene/ether togive 3-(4-chlorophenyl)-6-methoxy-1,2-benzisoxazole, mp 148°-9° C.

Analysis: Calculated for C₁₄ H₁₀ ClNO₂ : 64.86%C; 3.86%H. Found:64.49%C; 3.90%H.

EXAMPLE 91

a. A mixture of 60 g of pyridine hydrochloride and 12.0 g3-(4-chlorophenyl)-6-methoxy-1,2-benzisoxazole is heated with stirringat 210° C. for 75 min. The hot reaction mixture is poured with vigorousstirring onto ice and the solid is filtered, dried, and recrystallizedfrom toluene to afford 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole,mp 203° C.

Analysis: Calculated for C₁₃ H₈ ClNO₂ : 63.67%C; 3.26%H. Found: 63.39%C;3.27%H.

b. 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole is converted to6-(O,N,N-dimethylthiocarbamyl)-3-(4-chlorophenyl)-1,2-benzisoxazolewhich is thermally rearranged to6-(S,N,N-dimethylthiocarbamyl)-3-(4-chlorophenyl)-1,2-benzisoxazole andhydrolyzed to 3-(4-chlorophenyl)-6-mercapto-1,2-benzisoxazole, all stepsbeing performed according to the processes of Example 43.

EXAMPLE 92

To 29.8 g of 2,3-dichloro-4-methoxybenzoyl chloride in 150 ml of1,2-dichloroethane, 16.3 g of m-fluorophenetole is added. The solutionis chilled to 5° C. as 16.5 g of aluminum chloride is added slowly.After 2 hr, the reaction mixture is worked up with water and diethylether to give a mixture of2,3-dichloro-4'-ethoxy-2'-fluoro-4-methoxybenzophenone and2,3-dichloro-2'-ethoxy-4'-fluoro-4-methoxybenzophenone. The mixture isseparated by preparative high pressure liquid chromatography (10% ethylacetate/hexane 250 ml/min) to give2,3-dichloro-4'-ethoxy-2'-fluoro-4-methoxybenzophenone, mp 94°-96° C.

Analysis: Calculated for C₁₆ H₁₃ Cl₂ FO₃ : 55.99%C; 3.82%H. Found:55.86%C; 3.81%H.

EXAMPLE 93

A mixture of 26.7 g of2,3-dichloro-4'-ethoxy-2'-fluoro-4-methoxybenzophenone, in 250 ml ofpyridine and 18.0 g of hydroxylamine hydrochloride is heated underreflux overnight. Workup with 5% hydrochloric acid and diethyl ethergives diethyl ether insoluble product. The diethyl ether filtrate isevaporated and the residue hydrolyzed overnight in 150 ml of 1:1ethanol/water containing 15 g of sodium bisulfite. Workup with 5%hydrochloric acid/diethyl ether gives after filtration through silicagel (toluene) starting ketone. Repetition of the hydroxylaminehydrochloride in pyridine reaction gives additional Z-oxime.Recrystallization from toluene givesZ-2,3-Dichloro-4'-ethoxy-2'-fluoro-4-methoxybenzophenone oxime, mp188°-189° C.

Analysis: Calculated for C₁₆ H₁₄ Cl₂ FNO₃ : 53.65%C; 3.94%H; 3.91%N.Found: 53.66%C; 4.06%H; 3.77%N.

EXAMPLE 94

A solution of 23.3 g ofZ-2,3-dichloro-4'-ethoxy-2'-fluoro-4-methoxybenzophenone oxime in 175 mldimethylformamide is added to 1.85 g of sodium hydride in 35 ml ofdimethylformamide. After stirring 30 min at room temperature, thereaction is worked up with water and 1:1 diethyl ether/2-butanone.Concentration of the dried organic phase, trituration of the productwith hexane and recrystallization from toluene/hexane gives7-chloro-3-(4-ethoxy-2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp151°-152° C.

Analysis: Calculated for C₁₆ H₁₃ ClFNO₃ : 59.73%C; 4.07%H; 4.35%N.Found: 59.54%C; 4.13%H; 4.31%N.

EXAMPLE 95

To 29.8 g of 2,3-dichloro-4-methoxybenzoyl chloride in 150 ml of1,2-dichloroethane is added 16.3 g of m-fluorophenetole. The solution ischilled to 5° C. as 16.5 g of aluminum chloride is added slowly. After 2hr, the reaction mixture is worked up with water and diethyl ether togive a mixture of 2,3-dichloro-2'-ethoxy-4'fluoro-methoxybenzophenoneand 2,3-dichloro-4'-ethoxy-2'-fluoro-4-methoxybenzophenone. The mixtureis separated by preparative high pressure liquid chromatography (10%ethyl acetate/hexane; 250 ml/min) to give2,3-dichloro-2'-ethoxy-4'-fluoro-4-methoxybenzophenone, mp 107°-109° C.,after recrystallization from cyclohexane.

Analysis: Calculated for C₁₆ H₁₃ Cl₂ FO₃ : 55.99%C; 3.82%H. Found:55.83%C; 3.77%H.

EXAMPLE 96

a. A mixture of 12.0 g of2,3-dichloro-2'-ethoxy-4'-fluoro-4-methoxybenzophenone in 100 ml ofpyridine containing 7.0 g of hydroxylamine hydrochloride is heated underreflux for 3 hr. A standard work up with 5% hydrochloric acid anddiethyl ether gives E- andZ-2,3-dichloro-2'-ethoxy-4'-fluoro-4-methoxybenzophenone oxime. Themixture of oximes is dissolved in 60 ml of dimethylformamide and 40 mlof tetrahydrofuran and added to a suspension of 2.1 g of 50% sodiumhydride in 100 ml of tetrahydrofuran. The reaction mixture is refluxed2.5 hr. Workup with water and diethyl ether gives crystalline material.Two recrystallizations from acetonitrile give7-Chloro-3-(2-ethoxy-4-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp150°-152° C.

Analysis: Calculated for C₁₆ H₁₃ ClFNO₃ : 59.73%C; 4.07%H; 4.35%N.Found: 59.63%C; 4.11%H; 4.41%N.

b. 7-chloro-3-(2-ethoxy-4-fluorophenyl)-6-methoxy-1,2-benzisoxazole maybe demethylated to7-chloro-3-(2-ethoxy-4-fluorophenyl)-6-hydroxy-1,2-benzisoxazole whichmay be condensed ethyl bromoacetate to ethyl{[7-chloro-3-(2-ethoxy-4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate,both steps may be performed by the process of Example 74. Ethyl{[7-chloro-3-(2-ethoxy-4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetatemay be hydrolyzed to{[7-chloro-3-(2-ethoxy-4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid by the method of Example 64.

We claim:
 1. A compound depicted by the formula ##STR65## wherein R isnaphthyl, ##STR66## thienyl, furyl, pyrryl, pyridyl, or pyridyl N-oxide;R¹ is a free or esterified carboxyl group of 1 to 8 carbon atoms,##STR67## R², R³ and R⁴ are the same or different and each can behydrogen, halogen, or loweralkyl of 1 to 4 carbon atoms;X is hydrogen,halogen, loweralkyl of 1 to 4 carbon atoms, loweralkoxy of 1 to 4 carbonatoms, loweralkylthio of 1 to 4 carbon atoms, hydroxy, trifluoromethyl,nitro, amino or acylamino; R⁵, R⁶, R⁷, and R⁸ are the same or differentand can be hydrogen or loweralkyl of 1 to 4 carbon atoms; A and A' arethe same or different and can be O or S; and m and n are the same ordifferent and each can be the integer 1, 2 or 3; or a physiologicallyacceptable salt thereof.
 2. A compound according to claim 1 depicted bythe formula ##STR68##
 3. A compound according to claim 1 depicted by theformula ##STR69##
 4. A compound according to claim 1 depicted by theformula ##STR70##
 5. A compound according to claim 1 in which R is##STR71##
 6. A compound according to claim 5 depicted by the formula##STR72##
 7. A compound according to claim 6 in which R¹ is COOH.
 8. Acompound according to claim 5 depicted by the formula ##STR73##
 9. Acompound according to claim 8 in which R¹ is COOH.
 10. A compoundaccording to claim 5 depicted by the formula ##STR74##
 11. A compoundaccording to claim 10 in which R¹ is COOH.
 12. A compound according toclaim 1 in which A and A' are O.
 13. A compound according to claim 12depicted by the formula ##STR75##
 14. A compound according to claim 13in which R¹ is COOH.
 15. A compound according to claim 1 in which A is Sand A' is O.
 16. A compound according to claim 15 depicted by theformula ##STR76##
 17. A compound according to claim 16 in which R¹ isCOOH.
 18. A compound according to claim 1 in which A is O and A' is S.19. A compound according to claim 18 depicted by the formula ##STR77##20. A compound according to claim 19 in which R¹ is COOH.
 21. A compoundaccording to claim 1 in which R is thienyl, furyl, pyrryl, pyridyl orpyridyl N-oxide.
 22. A compound according to claim 1 depicted by theformula ##STR78##
 23. A compound according to claim 22 in which R¹ isCOOH.
 24. A compound according to claim 1 in which A and A' are S.
 25. Acompound according to claim 24 depicted by the formula ##STR79##
 26. Acompound according to claim 25 in which R¹ is COOH.
 27. The compounddefined in claim 1 which is{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid. 28.The compound defined in claim 1 which isethyl{[7-chloro-3-(2-thienyl)-1,2-benzisoxazole-6-yl]oxy}acetate. 29.The compound defined in claim 1 which isethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl)oxy}acetate.30. The compound defined in claim 1 which isethyl[(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetate.
 31. Thecompound defined in claim 1 which is[(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetic acid.
 32. Thecompound defined in claim 1 which isethyl{[7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 33. Thecompound defined in claim 1 which is{[7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
 34. Thecompound defined in claim 1 which is{[7-chloro-3-(3-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.35. The compound defined in claim 1 which isethyl{[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetate.36. The compound defined in claim 1 which is{[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.37. The compound defined in claim 1 which is ethyl{[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 38. Thecompound defined in claim 1 which is{[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
 39. Thecompound defined in claim 1 which is ethyl{[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 40. Thecompound defined in claim 1 which is{[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid. 41.The compound defined in claim 1 which is ethyl{[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetate. 42.The compound as defined in claim 1 which is{[7-chloro-3-(2-thienyl)-1,2-benzisoxazol-6-yl]-oxy}acetic acid.
 43. Thecompound as defined in claim 1 which is{[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.44. The compound as defined in claim 1 which is{[7-chloro-3-(3-furyl)-1,2-benziosoxazol-6-yl]oxy}acetic acid.
 45. Thecompound as defined in claim 1 which is{[7-chloro-3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.46. The compound as defined in claim 1 which is{[7-chloro-3-(trans-β-fluorostyryl-1,2-benzisoxazol-6-yl]oxy}aceticacid.
 47. The compound as defined in claim 1 which is{[7-chloro-3-(2,4-difluorophenyl)-1,2-benzisoxazol-6-yl]-oxy}aceticacid.
 48. The compound as defined in claim 1 which is{[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]-oxy}acetic acid.49. The compound as defined in claim 1 which is{[7-chloro-3-(3,4-dichlorophenyl)-1,2-benzisoxazol-6-yl]-oxy}aceticacid.
 50. The compound as defined in claim 1 which is{[7-chloro-3-(2-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid. 51.The compound as defined in claim 1 which is{[7-chloro-3-(2-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
 52. Thecompound as defined in claim 1 which is ethyl{[7-chloro-3-(1-naphthyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 53. Thecompound as defined in claim 1 which is{[7-chloro-3-(1-naphthyl)-1,2-benzisoxazol-6-yl]oxy}-acetic acid. 54.The compound as defined in claim 1 which isethyl{[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.55. The compound as defined in claim 1 which is{[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.56. The compound as defined in claim 1 which is{[7-chloro-3-(3-fluorophenyl)-1,2-benzisoxazol-6-yl]-oxy}acetic acid.57. The compound as defined in claim 1 which is{[7-chloro-3-(2-pyridyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
 58. Thecompound as defined in claim 1 which is{[7-chloro-3-(2-pyridyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid 1'-oxide.59. The compound as defined in claim 1 which is{[3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
 60. Thecompound as defined in claim 1 which is{[7-chloro-3-(4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid. 61.The compound as defined in claim 1 which is{[3-(2-fluorophenyl)-7-methyl-1,2-benzisoxazol-6-yl]oxy}acetic acid. 62.The compound as defined in claim 1 which is{[7-chloro-3-(4-chloro-2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid.
 63. The compound as defined in claim 1 which is{[3-(2-fluorophenyl)-7-iodo-1,2-benzisoxazol-6-yl]-oxy}acetic acid. 64.The compound as defined in claim 1 which is{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]-oxy}acetic acid. 65.The compound as defined in claim 1 which is ethyl{[3-benzyl-7-chloro-1,2-benzisoxazol-6-yl]oxy}-acetate.
 66. The compoundas defined in claim 1 which is{(3-benzyl-7-chloro-1,2-benzisoxazol-6-yl)oxy}acetic acid.
 67. Thecompound as defined in claim 1 which isethyl{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.68. The compound as defined in claim 1 which is {[5,7dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid. 69.The compound as defined in claim 1 which is ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio}acetate. 70.The compound as defined in claim 1 which is{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio aceticacid.
 71. The compound as defined in claim 1 which is{[4-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid. 72.The compound as defined in claim 1 which is{[7-chloro-3-(2,3-difluorophenyl)-1,2-benzisoxazol-6-yl]-oxy}aceticacid.
 73. The compound as defined in claim 1 which isethyl-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}propionate.74. The compound as defined in claim 1 which is2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}propionicacid.
 75. The compound as defined in claim 1 which is{[7-chloro-3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.76. The compound as defined in claim 1 which is[(7-chloro-1,2-benzisoxazol-6-yl)oxy]acetic acid.
 77. The compound asdefined in claim 1 which is{[7-chloro-3-(2-trifluoromethylphenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid.
 78. The compound as defined in claim 1 which is{[7-chloro-3-(2-hydroxyphenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.79. The compound as defined in claim 1 which is[4,5,7-trichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy aceticacid.
 80. The compound as defined in claim 1 which is[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy acetonitrile. 81.The compound as defined in claim 1 which isethyl-2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}-2-methylpropionate.
 82. The compound as defined in claim 1 which is{[7-chloro-3-(2-methoxy-5-nitrophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid.
 83. The compound as defined in claim 1 which is{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetohydroxamicacid.
 84. The compound as defined in claim 1 which is ethyl{[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}acetate.85. The compound as defined in claim 1 which isN-methyl-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide.86. The compound as defined in claim 1 which is{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide. 87.The compound as defined in claim 1 which is N,N-dimethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide. 88.The compound as defined in claim 1 which is{[3-(2-fluorophenyl)-4,5,7-trichloro-1,2-benzisoxazol-6-yl]oxy}aceticacid.
 89. The compound as defined in claim 1 which is ethyl{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 90. The compoundas defined in claim 1 which is ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}propionate.
 91. Thecompound as defined in claim 1 which is{[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid. 92.The compound as defined in claim 1 which is{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
 93. Thecompound as defined in claim 1 which is ethyl{[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 94. Thecompound as defined in claim 1 which is ethyl{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 95. Thecompound as defined in claim 1 which is ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}propionate.
 96. Thecompound as defined in claim 1 which is ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-2-methylpropionate.97. The compound as defined in claim 1 which is ethyl{[7-chloro-3-(2-fluoro-4-ethoxyphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.98. The compound as defined in claim 1 which is ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate.99. The compound as defined in claim 1 which is{[7-chloro-3-(2-fluoro-4-hydroxyphenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid.
 100. The compound as defined in claim 1 which is2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-2-methylpropionicacid.
 101. The compound as defined in claim 1 which is ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyrate.
 102. Thecompound as defined in claim 1 which is2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyric acid.
 103. Thecompound as defined in claim 1 which is2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionicacid.
 104. The compound as defined in claim 1 which is ethyl2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoate.
 105. Thecompound as defined in claim 1 which is2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}pentanoic acid. 106.The compound as defined in claim 1 which is ethyl2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionate.107. A compound as defined in claim 1 which is2-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio}-2-methylpropionicacid.
 108. A compound as defined in claim 1 which is{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetohydroxamicacid.
 109. A compound as defined in claim 1 which is ethyl{[3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 110. Acompound as defined in claim 1 which is{[3-(2,5-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
 111. Acompound as defined in claim 1 which is ethyl{[3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.
 112. Acompound as defined in claim 1 which is{[3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
 113. Acompound as defined in claim 1 which is ethyl{[7-chloro-3-(2-ethoxy-4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate.114. A compound as defined in claim 1 which is{[7-chloro-3-(2-ethoxy-4-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}aceticacid.